Aminopyrimidine derivatives as LRRK2 modulators

ABSTRACT

Compounds of the formula I: 
                         
or pharmaceutically acceptable salts thereof,
 
wherein m, n. X, R 1 , R 2 , R 3 , R 4  and R 5  are as defined herein. Also disclosed are methods of making the compounds and using the compounds for treatment of diseases associated with LRRK2 receptor, such as Parkinson&#39;s disease.

CROSS REFERENCE TO RELATED APPLICATION

This application claims the benefit under 35 USC §119 of U.S.Provisional Application Ser. No. 61/564,755 filed on Nov. 29, 2011, thedisclosure of which is incorporated herein by reference.

FIELD OF THE INVENTION

This invention pertains to compounds that modulate the function of LRRK2and are useful for treatment of LRRK2-mediated diseases and conditionssuch as Parkinson's disease.

BACKGROUND OF THE INVENTION

Neurodegenerative diseases such as Parkinson's disease, Lewy bodydementia and Huntington's disease affect millions of individuals.Parkinson's disease is a chronic, progressive motor system disorder thatafflicts approximately one out of every 1000 people, with hereditaryParkinson's disease accounting for 5-10% of all of patients. Parkinson'sdisease is caused by progressive loss of mid-brain dopamine neurons,leaving patients with impaired ability to direct and control theirmovements. The primary Parkinson's disease symptoms are trembling,rigidity, slowness of movement, and impaired balance. Many Parkinson'sdisease patients also experience other symptoms such as emotionalchanges, memory loss, speech problems, and sleeping disorders.

The gene encoding the leucine-rich repeat kinase 2 protein (LRRK2) hasbeen identified in association with hereditary Parkinson's disease(Paisan-Ruiz et al., Neuron, Vol. 44(4), 2004, pp 595-600; Zimprich etal., Neuron, Vol. 44(4), 2004, 601-607). In-vitro studies show thatParkinson's disease-associated mutation leads to increased LRRK2 kinaseactivity and decreased rate of GTP hydrolysis compared to wild-type (Guoet al., Experimental Cell Research, Vol. 313(16), 2007, pp. 3658-3670.Anti-LRRK2 antibodies have been used to label brainstem Lewy bodiesassociated with Parkinson's disease and cortical antibodies associatedwith Lewis body dementia suggesting that LRRK2 may play an importantrole in Lewie body formation and pathogenesis associated with thesediseases (Zhou et al., Molecular Degeneration, 2006, 1:17doi:10.1186/1750-1326-1-17). LRRK2 has also been identified as a genepotentially associated with increased susceptibility to Crohn's diseaseand susceptibility to leprosy (Zhang et al., New England J. Med. Vol.361 (2009) pp. 2609-2618.

LRRK2 has also been associated with the transition of mild cognitiveimpairment to Alzheimer's disease (WO2007/149789); L-Dopa induceddyskinesia (Hurley et al., Eur. J. Neurosci., Vol. 26, 2007, pp.171-177; CNS disorders associated with neuronal progenitordifferentiation (Milosevic et al., Neurodegen., Vol. 4, 2009, p. 25);cancers such as kidney, breast, prostate, blood and lung cancers andacute myelogenous leukemia (WO2011/038572); papillary renal and thyroidcarcinomas (Looyenga et al.,www.pnas.org/cgi/doi/10.1073/pnas.1012500108); multiple myeloma (Chapmanet al., Nature Vol. 471, 2011, pp. 467-472); amyotrophic lateralsclerosis (Shtilbans et al., Amyotrophic Lateral Sclerosis “Early Online2011, pp. 1-7); rheumatoid arthritis (Nakamura et al., DNA Res. Vol.13(4), 2006, pp. 169-183); and ankylosing spondylytis (Danoy et al.,PLoS Genetics, Vol. 6(12), 2010, e1001195, pp. 1-5).

Accordingly, compounds and compositions effective at modulating LRRK2activity may provide a treatment for neurodegenerative diseases such asParkinson's disease and Lewie body dementia, for CNS disorders such asAlzheimer's disease and L-Dopa induced dyskinesia, for cancers such askidney, breast, prostate, blood, papillary and lung cancers, acutemyelogenous leukemia and multiple myeloma, and for inflammatory diseasessuch as leprosy, Crohn's disease, amyotrophic lateral sclerosis,rheumatoid arthritis, and ankylosing spondylytis. Particularly, there isa need for compounds with LRRK2 affinity that are selective for LRRK2over other kinases, such as JAK2, and which can provide effective drugsfor treatment of neurodegenerative disorders such as Parkinson'sdisease.

SUMMARY OF THE INVENTION

The invention provides compounds of the formula I:

or pharmaceutically acceptable salts thereof,wherein:

m is from 0 to 3;

X is: —NR_(a)—; —O—; or —S(O)_(r)— wherein r is from 0 to 2 and R^(a) ishydrogen or C₁₋₆alkyl;

Y is C or N;

R¹ is: C₁₋₆alkyl; C₁₋₆alkenyl; C₁₋₆alkynyl; halo-C₁₋₆alkyl;C₁₋₆alkoxy-C₁₋₆alkyl; hydroxy-C₁₋₆alkyl; amino-C₁₋₆alkyl;C₁₋₆alkylsulfonyl-C₁₋₆alkyl; C₃₋₆cycloalkyl optionally substituted withC₁₋₆alkyl; C₃₋₆cycloalkyl-C₁₋₆alkyl wherein the C₃₋₆cycloalkyl portionis optionally substituted with C₁₋₆alkyl; tetrahydrofuranyl;tetrahydrofuranyl-C₁₋₆alkyl; oxetanyl; or oxetan-C₁₋₆alkyl;

or R¹ and R^(a) together with the atoms to which they are attached mayform a three to six membered ring that may optionally include anadditional heteroatom selected from O, N and S, and which is substitutedwith oxo, halo or C₁₋₆alkyl;

R² is: halo; C₁₋₆alkoxy; cyano; C₁₋₆alkynyl; C₁₋₆alkenyl;halo-C₁₋₆alkyl; halo-C₁₋₆alkoxy; C₃₋₆cycloalkyl wherein theC₃₋₆cycloalkyl portion is optionally substituted with C₁₋₆alkyl;C₃₋₆cycloalkyl-C₁₋₆alkyl wherein the C₃₋₆cycloalkyl portion isoptionally substituted with C₁₋₆alkyl; tetrahydrofuranyl;tetrahydrofuranyl-C₁₋₆alkyl; acetyl; oxetanyl; or oxetan-C₁₋₆alkyl;

R³ and R⁴ each independently is: halo; C₁₋₆alkyl; C₁₋₆alkoxy;C₃₋₆cycloalkyloxy; halo-C₁₋₆alkyl; or halo-C₁₋₆alkoxy; and

R⁵ is a 5-membered heteroaryl group optionally substituted one or moretimes with R⁶; and

R⁶ is: C₁₋₆alkyl; C₃₋₆cycloalkyl; C₃₋₆cycloalkyl-C₁₋₆alkyl; halo;halo-C₁₋₆alkyl; C₁₋₆alkoxy; heterocyclyl; oxo; or —C(O)—NR^(b)R^(c)wherein R^(b) and R^(c) each independently is hydrogen or —C₁₋₆alkyl.

The invention also provides and pharmaceutical compositions comprisingthe compounds, methods of using the compounds, and methods of preparingthe compounds.

DETAILED DESCRIPTION OF THE INVENTION Definitions

Unless otherwise stated, the following terms used in this application,including the specification and claims, have the definitions givenbelow. It must be noted that, as used in the specification and theappended claims, the singular forms “a”, “an,” and “the” include pluralreferents unless the context clearly dictates otherwise.

“Alkyl” means the monovalent linear or branched saturated hydrocarbonmoiety, consisting solely of carbon and hydrogen atoms, having from oneto twelve carbon atoms. “Lower alkyl” refers to an alkyl group of one tosix carbon atoms, i.e. C₁-C₆alkyl. Examples of alkyl groups include, butare not limited to, methyl, ethyl, propyl, isopropyl, isobutyl,sec-butyl, tert-butyl, pentyl, n-hexyl, octyl, dodecyl, and the like.

“Alkenyl” means a linear monovalent hydrocarbon radical of two to sixcarbon atoms or a branched monovalent hydrocarbon radical of three tosix carbon atoms, containing at least one double bond, e.g., ethenyl,propenyl, and the like.

“Alkynyl” means a linear monovalent hydrocarbon radical of two to sixcarbon atoms or a branched monovalent hydrocarbon radical of three tosix carbon atoms, containing at least one triple bond, e.g., ethynyl,propynyl, and the like.

“Alkylene” means a linear saturated divalent hydrocarbon radical of oneto six carbon atoms or a branched saturated divalent hydrocarbon radicalof three to six carbon atoms, e.g., methylene, ethylene,2,2-dimethylethylene, propylene, 2-methylpropylene, butylene, pentylene,and the like.

“Alkoxy” and “alkyloxy”, which may be used interchangeably, mean amoiety of the formula —OR, wherein R is an alkyl moiety as definedherein. Examples of alkoxy moieties include, but are not limited to,methoxy, ethoxy, isopropoxy, and the like.

“Alkoxyalkyl” means a moiety of the formula R^(a)—O—R^(b)—, where R^(a)is alkyl and R^(b) is alkylene as defined herein. Exemplary alkoxyalkylgroups include, by way of example, 2-methoxyethyl, 3-methoxypropyl,1-methyl-2-methoxyethyl, 1-(2-methoxyethyl)-3-methoxypropyl, and1-(2-methoxyethyl)-3-methoxypropyl.

“Alkoxyalkoxy’ means a group of the formula —O—R—R′ wherein R isalkylene and R′ is alkoxy as defined herein.

“Alkylcarbonyl” means a moiety of the formula —C(O)—R, wherein R isalkyl as defined herein.

“Alkoxycarbonyl” means a group of the formula —C(O)—R wherein R isalkoxy as defined herein.

“Alkylcarbonylalkyl” means a group of the formula —R—C(O)—R wherein R isalkylene and R′ is alkyl as defined herein.

“Alkoxycarbonylalkyl” means a group of the formula —R—C(O)—R wherein Ris alkylene and R′ is alkoxy as defined herein.

“Alkoxycarbonylalkoxy” means a group of the formula —O—R—C(O)—R′ whereinR is alkylene and R′ is alkoxy as defined herein.

“Hydroxycarbonylalkoxy” means a group of the formula —O—R—C(O)—OHwherein R is alkylene as defined herein.

“Alkylaminocarbonylalkoxy” means a group of the formula —O—R—C(O)—NHR′wherein R is alkylene and R′ is alkyl as defined herein.

“Dialkylaminocarbonylalkoxy” means a group of the formula—O—R—C(O)—NR′R″ wherein R is alkylene and R′ and R″ are alkyl as definedherein.

“Alkylaminoalkoxy” means a group of the formula —O—R—NHR′ wherein R isalkylene and R′ is alkyl as defined herein.

“Dialkylaminoalkoxy” means a group of the formula —O—R—NR′R′ wherein Ris alkylene and R′ and R″ are alkyl as defined herein.

“Alkylsulfonyl” means a moiety of the formula —SO₂—R, wherein R is alkylas defined herein.

“Alkylsulfonylalkyl means a moiety of the formula —R′—SO₂—R″ where whereR′ is alkylene and R″ is alkyl as defined herein.

“Alkylsulfonylalkoxy” means a group of the formula —O—R—SO₂—R′ wherein Ris alkylene and R′ is alkyl as defined herein.

“Amino means a moiety of the formula —NRR′ wherein R and R′ eachindependently is hydrogen or alkyl as defined herein. “Amino thusincludes “alkylamino (where one of R and R′ is alkyl and the other ishydrogen) and “dialkylamino (where R and R′ are both alkyl.

“Aminocarbonyl” means a group of the formula —C(O)—R wherein R is aminoas defined herein.

“Alkoxyamino” means a moiety of the formula —NR—OR′ wherein R ishydrogen or alkyl and R′ is alkyl as defined herein.

“Alkylsulfanyl” means a moiety of the formula —SR wherein R is alkyl asdefined herein.

“Aminoalkyl” means a group —R—R′ wherein R′ is amino and R is alkyleneas defined herein. “Aminoalkyl” includes aminomethyl, aminoethyl,1-aminopropyl, 2-aminopropyl, and the like. The amino moiety of“aminoalkyl” may be substituted once or twice with alkyl to provide“alkylaminoalkyl” and “dialkylaminoalkyl” respectively.“Alkylaminoalkyl” includes methylaminomethyl, methylaminoethyl,methylaminopropyl, ethylaminoethyl and the like. “Dialkylaminoalkyl”includes dimethylaminomethyl, dimethylaminoethyl, dimethylaminopropyl,N-methyl-N-ethylaminoethyl, and the like.

“Aminoalkoxy” means a group —OR—R′ wherein R′ is amino and R is alkyleneas defined herein.

“Alkylsulfonylamido” means a moiety of the formula —NR′SO₂—R wherein Ris alkyl and R′ is hydrogen or alkyl.

“Aminocarbonyloxyalkyl” or “carbamylalkyl” means a group of the formula—R—O—C(O)—NR′R″ wherein R is alkylene and R′, R″ each independently ishydrogen or alkyl as defined herein.

“Alkynylalkoxy” means a group of the formula —O—R—R′ wherein R isalkylene and R′ is alkynyl as defined herein.

“Aryl” means a monovalent cyclic aromatic hydrocarbon moiety consistingof a mono-, bi- or tricyclic aromatic ring. The aryl group can beoptionally substituted as defined herein. Examples of aryl moietiesinclude, but are not limited to, phenyl, naphthyl, phenanthryl,fluorenyl, indenyl, pentalenyl, azulenyl, oxydiphenyl, biphenyl,methylenediphenyl, aminodiphenyl, diphenylsulfidyl, diphenylsulfonyl,diphenylisopropylidenyl, benzodioxanyl, benzofuranyl, benzodioxylyl,benzopyranyl, benzoxazinyl, benzoxazinonyl, benzopiperadinyl,benzopiperazinyl, benzopyrrolidinyl, benzomorpholinyl,methylenedioxyphenyl, ethylenedioxyphenyl, and the like, of which may beoptionally substituted as defined herein.

“Arylalkyl” and “Aralkyl”, which may be used interchangeably, mean aradical-R^(a)R^(b) where R^(a) is an alkylene group and R^(b) is an arylgroup as defined herein; e.g., phenylalkyls such as benzyl, phenylethyl,3-(3-chlorophenyl)-2-methylpentyl, and the like are examples ofarylalkyl.

“Arylsulfonyl means a group of the formula —SO₂—R wherein R is aryl asdefined herein.

“Aryloxy” means a group of the formula —O—R wherein R is aryl as definedherein.

“Aralkyloxy” means a group of the formula —O—R—R″ wherein R is alkyleneand R′ is aryl as defined herein.

“Carboxy” or “hydroxycarbonyl”, which may be used interchangeably, meansa group of the formula —C(O)—OH.

“Cyanoalkyl” “means a moiety of the formula —R′—R″, where R′ is alkyleneas defined herein and R″ is cyano or nitrile.

“Cycloalkyl” means a monovalent saturated carbocyclic moiety consistingof mono- or bicyclic rings. Particular cycloalkyl are unsubstituted orsubstituted with alkyl. Cycloalkyl can optionally be substituted asdefined herein. Unless defined otherwise, cycloalkyl may be optionallysubstituted with one or more substituents, wherein each substituent isindependently hydroxy, alkyl, alkoxy, halo, haloalkyl, amino,monoalkylamino, or dialkylamino. Examples of cycloalkyl moietiesinclude, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, and the like, including partially unsaturated(cycloalkenyl) derivatives thereof.

“Cycloalkylalkyl” means a moiety of the formula —R′—R″, where R′ isalkylene and R″ is cycloalkyl as defined herein.

“Cycloalkylalkoxy” means a group of the formula —O—R—R′ wherein R isalkylene and R′ is cycloalkyl as defined herein.

“Heteroaryl” means a monocyclic or bicyclic radical of 5 to 12 ringatoms having at least one aromatic ring containing one, two, or threering heteroatoms selected from N, O, or S, the remaining ring atomsbeing C, with the understanding that the attachment point of theheteroaryl radical will be on an aromatic ring. The heteroaryl ring maybe optionally substituted as defined herein. Examples of heteroarylmoieties include, but are not limited to, optionally substitutedimidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl,thiadiazolyl, pyrazinyl, thienyl, benzothienyl, thiophenyl, furanyl,pyranyl, pyridyl, pyrrolyl, pyrazolyl, pyrimidyl, quinolinyl,isoquinolinyl, benzofuryl, benzothiophenyl, benzothiopyranyl,benzimidazolyl, benzooxazolyl, benzooxadiazolyl, benzothiazolyl,benzothiadiazolyl, benzopyranyl, indolyl, isoindolyl, triazolyl,triazinyl, quinoxalinyl, purinyl, quinazolinyl, quinolizinyl,naphthyridinyl, pteridinyl, carbazolyl, azepinyl, diazepinyl, acridinyland the like, each of which may be optionally substituted as definedherein.

Heteroarylalkyl” or “heteroaralkyl” means a group of the formula —R—R′wherein R is alkylene and R′ is heteroaryl as defined herein.

“Heteroarylsulfonyl means a group of the formula —SO₂—R wherein R isheteroaryl as defined herein.

“Heteroaryloxy” means a group of the formula —O—R wherein R isheteroaryl as defined herein.

“Heteroaralkyloxy” means a group of the formula —O—R—R″ wherein R isalkylene and R′ is heteroaryl as defined herein.

The terms “halo”, “halogen” and “halide”, which may be usedinterchangeably, refer to a substituent fluoro, chloro, bromo, or iodo.

“Haloalkyl” means alkyl as defined herein in which one or more hydrogenhas been replaced with same or different halogen. Exemplary haloalkylsinclude —CH₂Cl, —CH₂CF₃, —CH₂CCl₃, perfluoroalkyl (e.g., —CF₃), and thelike.

“Haloalkoxy” means a moiety of the formula —OR, wherein R is a haloalkylmoiety as defined herein. An exemplary haloalkoxy is difluoromethoxy.

“Heterocycloamino” means a saturated ring wherein at least one ring atomis N, NH or N-alkyl and the remaining ring atoms form an alkylene group.

“Heterocyclyl” means a monovalent saturated moiety, consisting of one tothree rings, incorporating one, two, or three or four heteroatoms(chosen from nitrogen, oxygen or sulfur). The heterocyclyl ring may beoptionally substituted as defined herein. Examples of heterocyclylmoieties include, but are not limited to, optionally substitutedpiperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, azepinyl,pyrrolidinyl, azetidinyl, tetrahydropyranyl, tetrahydrofuranyl, oxetanyland the like. Such heterocyclyl may be optionally substituted as definedherein.

“Heterocyclylalkyl” means a moiety of the formula —R—R′ wherein R isalkylene and R′ is heterocyclyl as defined herein.

“Heterocyclyloxy” means a moiety of the formula —OR wherein R isheterocyclyl as defined herein.

“Heterocyclylalkoxy” means a moiety of the formula —OR—R′ wherein R isalkylene and R′ is heterocyclyl as defined herein.

“Heterocyclylsulfonyl” means a group of formula —SO₂—R wherein R isheterocyclyl as defined herein.

“Hydroxyalkoxy” means a moiety of the formula —OR wherein R ishydroxyalkyl as defined herein.

“Hydroxyalkylamino” means a moiety of the formula —NR—R′ wherein R ishydrogen or alkyl and R′ is hydroxyalkyl as defined herein.

“Hydroxyalkylaminoalkyl” means a moiety of the formula —R—NR′—R″ whereinR is alkylene, R′ is hydrogen or alkyl, and R″ is hydroxyalkyl asdefined herein.

“Hydroxycarbonylalkyl” or “carboxyalkyl” means a group of the formula—R—(CO)—OH where R is alkylene as defined herein.

“Hydroxycarbonylalkoxy” means a group of the formula —O—R—C(O)—OHwherein R is alkylene as defined herein.

“Hydroxyalkyloxycarbonylalkyl” or “hydroxyalkoxycarbonylalkyl” means agroup of the formula —R—C(O)—O—R—OH wherein each R is alkylene and maybe the same or different.

“Hydroxyalkyl” means an alkyl moiety as defined herein, substituted withone or more, for example, one, two or three hydroxy groups, providedthat the same carbon atom does not carry more than one hydroxy group.Representative examples include, but are not limited to, hydroxymethyl,2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl,1-(hydroxymethyl)-2-methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl,4-hydroxybutyl, 2,3-dihydroxypropyl, 2-hydroxy-1-hydroxymethylethyl,2,3-dihydroxybutyl, 3,4-dihydroxybutyl and2-(hydroxymethyl)-3-hydroxypropyl

“Hydroxycycloalkyl” means a cycloalkyl moiety as defined herein whereinone, two or three hydrogen atoms in the cycloalkyl radical have beenreplaced with a hydroxy substituent. Representative examples include,but are not limited to, 2-, 3-, or 4-hydroxycyclohexyl, and the like.

“Alkoxy hydroxyalkyl” and “hydroxy alkoxyalkyl”, which may be usedinterchangeably, means an alkyl as defined herein that is substituted atleast once with hydroxy and at least once with alkoxy. “Alkoxyhydroxyalkyl” and “hydroxy alkoxyalkyl” thus encompass, for example,2-hydroxy-3-methoxy-propan-1-yl and the like.

“Urea” or “ureido” means a group of the formula —NR′—C(O)—NR″R′″ whereinR′, R″ and R′″ each independently is hydrogen or alkyl.

“Carbamate” means a group of the formula —O—C(O)—NR′R″ wherein R′ and R″each independently is hydrogen or alkyl.

“Carboxy” means a group of the formula —O—C(O)—OH.

“Sulfonamido” means a group of the formula —SO₂—NR′R″ wherein R′, R″ andR′″ each independently is hydrogen or alkyl.

“Optionally substituted” when used in association with an “aryl”,phenyl”, “heteroaryl” “cycloalkyl” or “heterocyclyl” moiety means thatsuch moiety may be unsubstituted (i.e., all open valencies are occupiedby a hydrogen atom) or substituted with specific groups as relatedherein.

“Leaving group” means the group with the meaning conventionallyassociated with it in synthetic organic chemistry, i.e., an atom orgroup displaceable under substitution reaction conditions. Examples ofleaving groups include, but are not limited to, halogen, alkane- orarylenesulfonyloxy, such as methanesulfonyloxy, ethanesulfonyloxy,thiomethyl, benzenesulfonyloxy, tosyloxy, and thienyloxy,dihalophosphinoyloxy, optionally substituted benzyloxy, isopropyloxy,acyloxy, and the like.

“Modulator” means a molecule that interacts with a target. Theinteractions include, but are not limited to, agonist, antagonist, andthe like, as defined herein.

“Optional” or “optionally” means that the subsequently described eventor circumstance may but need not occur, and that the descriptionincludes instances where the event or circumstance occurs and instancesin which it does not.

“Disease” and “Disease state” means any disease, condition, symptom,disorder or indication.

“Inert organic solvent” or “inert solvent” means the solvent is inertunder the conditions of the reaction being described in conjunctiontherewith, including for example, benzene, toluene, acetonitrile,tetrahydrofuran, N,N-dimethylformamide, chloroform, methylene chlorideor dichloromethane, dichloroethane, diethyl ether, ethyl acetate,acetone, methyl ethyl ketone, methanol, ethanol, propanol, isopropanol,tert-butanol, dioxane, pyridine, and the like. Unless specified to thecontrary, the solvents used in the reactions of the present inventionare inert solvents.

“Pharmaceutically acceptable” means that which is useful in preparing apharmaceutical composition that is generally safe, non-toxic, andneither biologically nor otherwise undesirable and includes that whichis acceptable for veterinary as well as human pharmaceutical use.

“Pharmaceutically acceptable salts” of a compound means salts that arepharmaceutically acceptable, as defined herein, and that possess thedesired pharmacological activity of the parent compound.

It should be understood that all references to pharmaceuticallyacceptable salts include solvent addition forms (solvates) or crystalforms (polymorphs) as defined herein, of the same acid addition salt.

“Protective group” or “protecting group” means the group whichselectively blocks one reactive site in a multifunctional compound suchthat a chemical reaction can be carried out selectively at anotherunprotected reactive site in the meaning conventionally associated withit in synthetic chemistry. Certain processes of this invention rely uponthe protective groups to block reactive nitrogen and/or oxygen atomspresent in the reactants. For example, the terms “amino-protectinggroup” and “nitrogen protecting group” are used interchangeably hereinand refer to those organic groups intended to protect the nitrogen atomagainst undesirable reactions during synthetic procedures. Exemplarynitrogen protecting groups include, but are not limited to,trifluoroacetyl, acetamido, benzyl (Bn), benzyloxycarbonyl(carbobenzyloxy, CBZ), p-methoxybenzyloxycarbonyl,p-nitrobenzyloxycarbonyl, tert-butoxycarbonyl (BOC), and the like. Theartisan in the art will know how to chose a group for the ease ofremoval and for the ability to withstand the following reactions.

“Solvates” means solvent additions forms that contain eitherstoichiometric or non stoichiometric amounts of solvent. Some compoundshave a tendency to trap a fixed molar ratio of solvent molecules in thecrystalline solid state, thus forming a solvate. If the solvent is waterthe solvate formed is a hydrate, when the solvent is alcohol, thesolvate formed is an alcoholate. Hydrates are formed by the combinationof one or more molecules of water with one of the substances in whichthe water retains its molecular state as H₂O, such combination beingable to form one or more hydrate.

“Parkinson's disease” means a degenerative disorder of the centralnervous system that impairs motor skills, speech, and/or cognitivefunction. Symptoms of Parkinson's disease may include, for example,muscle rigidity, tremor, slowing of physical movement (bradykinesia) andloss of physical movement (akinesia).

“Lewie body disease” also called “Lewie body dementia”, diffuse Lewybody disease”, cortical Lewie body disease”, means a neurogenerativedisorder characterized anatomically by the presence of Lewie bodies inthe brain.

“Subject” means mammals and non-mammals. Mammals means any member of themammalia class including, but not limited to, humans; non-human primatessuch as chimpanzees and other apes and monkey species; farm animals suchas cattle, horses, sheep, goats, and swine; domestic animals such asrabbits, dogs, and cats; laboratory animals including rodents, such asrats, mice, and guinea pigs; and the like. Examples of non-mammalsinclude, but are not limited to, birds, and the like. The term “subject”does not denote a particular age or sex.

“Therapeutically effective amount” means an amount of a compound that,when administered to a subject for treating a disease state, issufficient to effect such treatment for the disease state. The“therapeutically effective amount” will vary depending on the compound,disease state being treated, the severity or the disease treated, theage and relative health of the subject, the route and form ofadministration, the judgment of the attending medical or veterinarypractitioner, and other factors.

The terms “those defined above” and “those defined herein” whenreferring to a variable incorporates by reference the broad definitionof the variable as well as particular definitions, if any.

“Treating” or “treatment” of a disease state includes, inter alia,inhibiting the disease state, i.e., arresting the development of thedisease state or its clinical symptoms, and/or relieving the diseasestate, i.e., causing temporary or permanent regression of the diseasestate or its clinical symptoms.

The terms “treating”, “contacting” and “reacting” when referring to achemical reaction means adding or mixing two or more reagents underappropriate conditions to produce the indicated and/or the desiredproduct. It should be appreciated that the reaction which produces theindicated and/or the desired product may not necessarily result directlyfrom the combination of two reagents which were initially added, i.e.,there may be one or more intermediates which are produced in the mixturewhich ultimately leads to the formation of the indicated and/or thedesired product.

Nomenclature and Structures

In general, the nomenclature and chemical names used in this applicationare based on ChembioOffice™ by CambridgeSoft™. Any open valencyappearing on a carbon, oxygen sulfur or nitrogen atom in the structuresherein indicates the presence of a hydrogen atom unless indicatedotherwise. Where a nitrogen-containing heteroaryl ring is shown with anopen valency on a nitrogen atom, and variables such as R^(a), R^(b) orR^(c) are shown on the heteroaryl ring, such variables may be bound orjoined to the open valency nitrogen. Where a chiral center exists in astructure but no specific stereochemistry is shown for the chiralcenter, both enantiomers associated with the chiral center areencompassed by the structure. Where a structure shown herein may existin multiple tautomeric forms, all such tautomers are encompassed by thestructure. The atoms represented in the structures herein are intendedto encompass all naturally occurring isotopes of such atoms. Thus, forexample, the hydrogen atoms represented herein are meant to includedeuterium and tritium, and the carbon atoms are meant to include C¹³ andC¹⁴ isotopes.

Compounds of the Invention

The invention provides compounds of the formula I:

or pharmaceutically acceptable salts thereof,wherein:

m is from 0 to 3;

X is: —NR^(a)—; —O—; or —S(O)_(r)— wherein r is from 0 to 2 and R^(a) ishydrogen or C₁₋₆alkyl;

Y is C or N;

R¹ is: C₁₋₆alkyl; C₁₋₆alkenyl; C₁₋₆alkynyl; halo-C₁₋₆alkyl;C₁₋₆alkoxy-C₁₋₆alkyl; hydroxy-C₁₋₆alkyl; amino-C₁₋₆alkyl;C₁₋₆alkylsulfonyl-C₁₋₆alkyl; C₃₋₆cycloalkyl optionally substituted withC₁₋₆alkyl; C₃₋₆cycloalkyl-C₁₋₆alkyl wherein the C₃₋₆cycloalkyl portionis optionally substituted with C₁₋₆alkyl; tetrahydrofuranyl;tetrahydrofuranyl-C₁₋₆alkyl; oxetanyl; or oxetan-C₁₋₆alkyl;

or R¹ and R^(a) together with the atoms to which they are attached mayform a three to six membered ring that may optionally include anadditional heteroatom selected from O, N and S, and which is substitutedwith oxo, halo or C₁₋₆alkyl;

R² is: halo; C₁₋₆alkoxy; cyano; C₁₋₆alkynyl; C₁₋₆alkenyl;halo-C₁₋₆alkyl; halo-C₁₋₆alkoxy; C₃₋₆cycloalkyl wherein theC₃₋₆cycloalkyl portion is optionally substituted with C₁₋₆alkyl;C₃₋₆cycloalkyl-C₁₋₆alkyl wherein the C₃₋₆cycloalkyl portion isoptionally substituted with C₁₋₆alkyl; tetrahydrofuranyl;tetrahydrofuranyl-C₁₋₆alkyl; acetyl; oxetanyl; or oxetan-C₁₋₆alkyl;

R³ and R⁴ each independently is: halo; C₁₋₆alkyl; C₁₋₆alkoxy;C₃₋₆cycloalkyloxy; halo-C₁₋₆alkyl; or halo-C₁₋₆alkoxy; and

R⁵ is a 5-membered heteroaryl group optionally substituted one or moretimes with R⁶; and

R⁶ is: C₁₋₆alkyl; C₃₋₆cyclo alkyl; C₃₋₆cycloalkyl-C₁₋₆alkyl; halo;halo-C₁₋₆alkyl; C₁₋₆alkoxy; heterocyclyl; oxo; or —C(O)—NR^(b)R^(c)wherein R^(b) and R^(c) each independently is hydrogen or —C₁₋₆alkyl.

In certain embodiments of formula I, R¹ and R^(a) together with theatoms to which they are attached may form a three to six membered ringthat may optionally include an additional heteroatom selected from O, Nand S, and which may be optionally substituted with oxo, halo orC₁₋₆alkyl.

In certain embodiments of formula I, R¹ and R^(a) together with theatoms to which they are attached form a five or six membered ring.

In certain embodiments of formula I, R¹ and R^(a) together with theatoms to which they are attached form a pyrrolidinyl, piperidinyl oroxazoladinonyl group.

In certain embodiments of formula I, R² is acetyl.

In certain embodiments of formula I, when R¹ is cyclopropyl, cyclobutyl,cyclopropyl-C₁₋₆alkyl or cyclobutyl-C₁₋₆alkyl, then X is —O—.

In certain embodiments of formula I, m is from 0 to 2.

In certain embodiments of formula I, m is 0 or 1.

In certain embodiments of formula I, m is 0.

In certain embodiments of formula I, m is 1.

In certain embodiments of formula I, r is 0.

In certain embodiments of formula I, r is 2.

In certain embodiments of formula I, X is —NR^(a)— or —O—.

In certain embodiments of formula I, X is —NR^(a).

In certain embodiments of formula I, X is —O—.

In certain embodiments of formula I, X is —S(O)_(n)—.

In certain embodiments of formula I, X is —NH— or —O—.

In certain embodiments of formula I, Y is C.

In certain embodiments of formula I, Y is N.

In certain embodiments of formula I, R^(a) is hydrogen.

In certain embodiments of formula I, R^(a) is C₁₋₆alkyl.

In certain embodiments of formula I, R¹ is: C₁₋₆alkyl; halo-C₁₋₆alkyl;C₁₋₆alkoxy-C₁₋₆alkyl; amino-C₁₋₆alkyl; C₁₋₆alkylsulfonyl-C₁₋₆alkyl;C₃₋₆cycloalkyl; or C₃₋₆cycloalkyl-C₁₋₆alkyl.

In certain embodiments of formula I, R¹ is: C₁₋₆alkyl; C₃₋₆cycloalkyloptionally substituted with C₁₋₆alkyl; or C₃₋₆cycloalkyl-C₁₋₆alkylwherein the C₃₋₆cycloalkyl portion is optionally substituted withC₁₋₆alkyl.

In certain embodiments of formula I, R¹ is: C₁₋₆alkyl; halo-C₁₋₆alkyl;C₁₋₆alkoxy-C₁₋₆alkyl; amino-C₁₋₆alkyl; C₁₋₆alkylsulfonyl-C₁₋₆alkyl;tetrahydrofuranyl; tetrahydrofuranyl-C₁₋₆alkyl; oxetanyl; oroxetan-C₁₋₆alkyl.

In certain embodiments of formula I, R¹ is: C₁₋₆alkyl; halo-C₁₋₆alkyl;C₁₋₆alkoxy-C₁₋₆alkyl; amino-C₁₋₆alkyl; or C₁₋₆alkylsulfonyl-C₁₋₆alkyl.

In certain embodiments of formula I, R¹ is C₁₋₆alkyl.

In certain embodiments of formula I, R¹ is halo-C₁₋₆alkyl.

In certain embodiments of formula I, R¹ is C₁₋₆alkoxy-C₁₋₆alkyl.

In certain embodiments of formula I, R¹ is amino-C₁₋₆alkyl.

In certain embodiments of formula I, R¹ is C₁₋₆alkylsulfonyl-C₁₋₆alkyloptionally substituted with C₁₋₆alkyl.

In certain embodiments of formula I, R¹ is C₃₋₆cycloalkyl optionallysubstituted with C₁₋₆alkyl.

In certain embodiments of formula I, R¹ is C₃₋₆cycloalkyl-C₁₋₆alkylwherein the C₃₋₆cycloalkyl portion is optionally substituted withC₁₋₆alkyl.

In certain embodiments of formula I, R¹ is tetrahydrofuranyl.

In certain embodiments of formula I, R¹ is tetrahydrofuranyl-C₁₋₆alkyl;oxetanyl.

In certain embodiments of formula I, R¹ is or oxetan-C₁₋₆alkyl.

In certain embodiments of formula I, R¹ is: methyl; ethyl; n-propyl;isopropyl; isobutyl; 3,3-dimethylpropyl; cyclopropyl; cyclobutyl;cyclopentyl; cyclohexyl; cyclopropylmethyl; cyclobutylmethyl;cyclopentylmethyl; cyclopropylethyl; methoxyethyl; oxetanyl; ortetrahydrofuranylmethyl.

In certain embodiments of formula I, R¹ is: methyl; ethyl; n-propyl;isopropyl; isobutyl; 3,3-dimethylpropyl; cyclopentyl; cyclohexyl;cyclopropylmethyl; cyclobutylmethyl; cyclopentylmethyl;cyclopropylethyl; methoxyethyl; oxetanyl; or tetrahydrofuranylmethyl.

In certain embodiments of formula I, R¹ is: methyl; ethyl; n-propyl;isopropyl; isobutyl; 3,3-dimethylpropyl; cyclopentyl; cyclohexyl;cyclopentylmethyl; methoxyethyl; oxetanyl; or tetrahydrofuranylmethyl.

In certain embodiments of formula I, R¹ is: methyl; ethyl; n-propyl;isopropyl; or isobutyl.

In certain embodiments of formula I, R¹ is methyl or ethyl.

In certain embodiments of formula I, R¹ is methyl.

In certain embodiments of formula I, R¹ is ethyl.

In certain embodiments of formula I, R¹ is: cyclopropyl; cyclobutyl;cyclopentyl; cyclohexyl; cyclopropylmethyl; cyclobutylmethyl;cyclopentylmethyl; or cyclopropylethyl.

In certain embodiments of formula I, R¹ is: cyclopentyl; cyclohexyl; orcyclopentylmethyl.

In certain embodiments of formula I, R² is: halo; C₁₋₆alkoxy;halo-C₁₋₆alkyl; halo-C₁₋₆alkoxy; C₃₋₆cycloalkyl wherein theC₃₋₆cycloalkyl portion is optionally substituted with C₁₋₆alkyl;C₃₋₆cycloalkyl-C₁₋₆alkyl wherein the C₃₋₆cycloalkyl portion isoptionally substituted with C₁₋₆alkyl; tetrahydrofuranyl;tetrahydrofuranyl-C₁₋₆alkyl; oxetanyl; or oxetan-C₁₋₆alkyl.

In certain embodiments of formula I, R² is: halo; C₁₋₆alkoxy;halo-C₁₋₆alkyl; cyano; C₁₋₆alkynyl; C₁₋₆alkenyl; C₃₋₆cycloalkyl; orC₃₋₆cycloalkyl-C₁₋₆alkyl.

In certain embodiments of formula I, R² is: halo; C₁₋₆alkoxy;halo-C₁₋₆alkyl; cyano; C₃₋₆cycloalkyl; or C₃₋₆cycloalkyl-C₁₋₆alkyl.

In certain embodiments of formula I, R² is: halo; C₁₋₆alkoxy;halo-C₁₋₆alkyl; C₃₋₆cycloalkyl; or C₃₋₆cycloalkyl-C₁₋₆alkyl.

In certain embodiments of formula I, R² is: halo; halo-C₁₋₆alkyl; orcyano.

In certain embodiments of formula I, R² is: halo; or halo-C₁₋₆alkyl.

In certain embodiments of formula I, R² is halo.

In certain embodiments of formula I, R² is C₁₋₆alkoxy.

In certain embodiments of formula I, R² is halo-C₁₋₆alkoxy.

In certain embodiments of formula I, R² is halo-C₁₋₆alkyl.

In certain embodiments of formula I, R² is C₃₋₆cycloalkyl.

In certain embodiments of formula I, R² is C₃₋₆cycloalkyl-C₁₋₆alkyl.

In certain embodiments of formula I, R² is tetrahydrofuranyl.

In certain embodiments of formula I, R² is tetrahydrofuranyl-C₁₋₆alkyl.

In certain embodiments of formula I, R² is oxetanyl.

In certain embodiments of formula I, R² is oxetan-C₁₋₆alkyl.

In certain embodiments of formula I, R² is halo, trifluoromethyl orcyano.

In certain embodiments of formula I, R² is chloro, trifluoromethyl orcyano.

In certain embodiments of formula I, R² is chloro or trifluoromethyl.

In certain embodiments of formula I, R² is fluoro, chloro or bromo.

In certain embodiments of formula I, R² is chloro.

In certain embodiments of formula I, R² is fluoro.

In certain embodiments of formula I, R² is bromo.

In certain embodiments of formula I, R² is trifluoromethyl.

In certain embodiments of formula I, R² is methoxy.

In certain embodiments of formula I, R² is cyano.

In certain embodiments of formula I, R² is C₁₋₆alkynyl.

In certain embodiments of formula I, R² is C₁₋₆alkenyl.

In certain embodiments of formula I, R³ is: C₁₋₆alkyl;

In certain embodiments of formula I, R³ is halo.

In certain embodiments of formula I, R³ is C₁₋₆alkyl.

In certain embodiments of formula I, R³ is C₁₋₆alkoxy.

In certain embodiments of formula I, R³ is halo or C₁₋₆alkoxy.

In certain embodiments of formula I, R³ is C₃₋₆cycloalkyloxy.

In certain embodiments of formula I, R³ is halo-C₁₋₆alkyl.

In certain embodiments of formula I, R³ is halo-C₁₋₆alkoxy.

In certain embodiments of formula I, R³ is halo or methoxy.

In certain embodiments of formula I, R³ is fluoro, chloro or methoxy.

In certain embodiments of formula I, R³ is fluoro or chloro.

In certain embodiments of formula I, R³ is methoxy.

In certain embodiments of formula I, R³ is methyl

In certain embodiments of formula I, R³ is chloro.

In certain embodiments of formula I, R³ is fluoro.

In certain embodiments of formula I, R⁴ is: C₁₋₆alkyl;

In certain embodiments of formula I, R⁴ is halo.

In certain embodiments of formula I, R⁴ is C₁₋₆alkyl.

In certain embodiments of formula I, R⁴ is C₁₋₆alkoxy.

In certain embodiments of formula I, R⁴ is halo-C₁₋₆alkyl.

In certain embodiments of formula I, R⁴ is halo-C₁₋₆alkoxy.

In certain embodiments of formula I, R⁴ is halo or methoxy.

In certain embodiments of formula I, R⁴ is R⁴ is fluoro, chloro, methylor methoxy.

In certain embodiments of formula I, R⁴ is fluoro, chloro or methoxy.

In certain embodiments of formula I, R⁴ is fluoro or chloro.

In certain embodiments of formula I, R⁴ is methoxy.

In certain embodiments of formula I, R⁴ is methyl

In certain embodiments of formula I, R⁴ is chloro.

In certain embodiments of formula I, R⁴ is fluoro.

In certain embodiments of formula I, R⁴ is C₃₋₆cycloalkyloxy.

In certain embodiments of formula I, R⁵ is: oxazolyl; thiazolyl;pyrazolyl; imidazolyl; isoxazolyl; isothiazolyl; oxadiazolyl;thiadiazolyl; triazolyl; or tetrazolyl; each optionally substituted oneor more times with R⁶.

In certain embodiments of formula I, R⁵ is: pyrazolyl; imidazolyl;oxadiazolyl; thiadiazolyl; triazolyl; or tetrazolyl; each optionallysubstituted one or more times with R⁶.

In certain embodiments of formula I, R⁵ is: pyrazolyl; oxadiazolyl;triazolyl; or tetrazolyl; each optionally substituted one or more timeswith R⁶.

In certain embodiments of formula I, R⁵ is: oxadiazolyl; triazolyl; ortetrazolyl; each optionally substituted one or more times with R⁶.

In certain embodiments of formula I, R⁵ is oxazolyl optionallysubstituted one or more times with R⁶.

In certain embodiments of formula I, R⁵ is thiazolyl optionallysubstituted one or more times with R⁶.

In certain embodiments of formula I, R⁵ is pyrazolyl optionallysubstituted one or more times with R⁶.

In certain embodiments of formula I, R⁵ is imidazolyl optionallysubstituted one or more times with R⁶.

In certain embodiments of formula I, R⁵ is isoxazolyl optionallysubstituted one or more times with R⁶.

In certain embodiments of formula I, R⁵ is isothiazolyl optionallysubstituted one or more times with R⁶.

In certain embodiments of formula I, R⁵ is oxadiazolyl; thiadiazolyl;triazolyl; or tetrazolyl; optionally substituted one or more times withR⁶.

In certain embodiments of formula I, R⁵ is thiadiazolyl optionallysubstituted one or more times with R⁶.

In certain embodiments of formula I, R⁵ is triazolyl optionallysubstituted one or more times with R⁶.

In certain embodiments of formula I, R⁵ is tetrazolyl optionallysubstituted one or more times with R⁶.

In certain embodiments of formula I, R⁵ is thiazol-5-yl optionallysubstituted one or more times with R⁶.

In certain embodiments of formula I, R⁵ is thiazol-4-yl optionallysubstituted one or more times with R⁶.

In certain embodiments of formula I, R⁵ is thiazol-2-yl optionallysubstituted one or more times with R⁶.

In certain embodiments of formula I, R⁵ is oxazol-5-yl optionallysubstituted one or more times with R⁶.

In certain embodiments of formula I, R⁵ is oxazol-4-yl optionallysubstituted one or more times with R⁶.

In certain embodiments of formula I, R⁵ is oxazol-2-yl optionallysubstituted one or more times with R⁶.

In certain embodiments of formula I, R⁵ is isothiazol-2-yl optionallysubstituted one or more times with R⁶.

In certain embodiments of formula I, R⁵ is isothiazol-3-yl optionallysubstituted one or more times with R⁶.

In certain embodiments of formula I, R⁵ is isothiazol-4-yl optionallysubstituted one or more times with R⁶.

In certain embodiments of formula I, R⁵ is isoxazol-2-yl optionallysubstituted one or more times with R⁶.

In certain embodiments of formula I, R⁵ is isoxazol-3-yl optionallysubstituted one or more times with R⁶.

In certain embodiments of formula I, R⁵ is isoxazol-4-yl optionallysubstituted one or more times with R⁶.

In certain embodiments of formula I, R⁵ is imidazol-2-yl optionallysubstituted one or more times with R⁶.

In certain embodiments of formula I, R⁵ is imidazol-1-yl optionallysubstituted one or more times with R⁶.

In certain embodiments of formula I, R⁵ is imidazol-4-yl optionallysubstituted one or more times with R⁶.

In certain embodiments of formula I, R⁵ is imidazol-5-yl optionallysubstituted one or more times with R⁶.

In certain embodiments of formula I, R⁵ is pyrazol-1-yl optionallysubstituted one or more times with R⁶.

In certain embodiments of formula I, R⁵ is pyrazol-3-yl optionallysubstituted one or more times with R⁶.

In certain embodiments of formula I, R⁵ is pyrazol-4-yl optionallysubstituted one or more times with R⁶.

In certain embodiments of formula I, R⁵ is pyrazol-5-yl optionallysubstituted one or more times with R⁶.

In certain embodiments of formula I, R⁵ is 1,2,3-triazol-1-yl optionallysubstituted one or more times with R⁶.

In certain embodiments of formula I, R⁵ is 1,2,3-triazol-4-yl optionallysubstituted one or more times with R⁶.

In certain embodiments of formula I, R⁵ is 1,2,3-triazol-5-yl optionallysubstituted one or more times with R⁶.

In certain embodiments of formula I, R⁵ is 1,2,4-triazol-1-yl optionallysubstituted one or more times with R⁶.

In certain embodiments of formula I, R⁵ is 1,2,4-triazol-3-yl optionallysubstituted one or more times with R⁶.

In certain embodiments of formula I, R⁵ is 1,2,4-triazol-5-yl optionallysubstituted one or more times with R⁶.

In certain embodiments of formula I, R⁵ is 1,3,4-oxadiazol-2-yloptionally substituted with R⁶.

In certain embodiments of formula I, R⁵ is 1,2,4-oxadiazol-3-yloptionally substituted with R⁶.

In certain embodiments of formula I, R⁵ is 1,2,4-oxadiazol-5-yloptionally substituted with R⁶.

In certain embodiments of formula I, R⁵ is 1,3,4-thiadiazol-2-yloptionally substituted with R⁶.

In certain embodiments of formula I, R⁵ is 1,2,4-thiadiazol-3-yloptionally substituted with R⁶.

In certain embodiments of formula I, R⁵ is 1,2,4-thiadiazol-5-yloptionally substituted with R⁶.

In certain embodiments of formula I, R⁵ is tetrazol-1-yl optionallysubstituted with R⁶.

In certain embodiments of formula I, R⁵ is tetrazol-5-yl optionallysubstituted with R⁶.

In certain embodiments of formula I, R⁵ is: thiazol-5-yl; thiazol-4-yl;oxazol-2-yl; isoxazol-4-y; 3,5-dimethylisoxazol-4-yl;1-methyl-1H-imidazol-2-yl; 1-methyl-1H-imidazol-5-yl;1,3,5-trimethyl-1H-pyrazol-4-yl; 1-methyl-1H-pyrazol-5-yl;1-methyl-1H-pyrazol-4-yl; 1,3-dimethyl-1H-pyrazol-4-yl;1,5-dimethyl-1H-pyrazol-4-yl;5-(dimethylaminocarbonyl)-1-methyl-1H-pyrazol-4-yl;1-(oxetan-3-yl)-1H-pyrazol-4-yl;5-(methoxymethyl)-3-methyl-1H-pyrazol-1-yl;1-methyl-1H-1,2,3-triazol-5-yl; 1H-1,2,4-triazol-1-yl;4-methyl-4H-1,2,4-triazol-3-yl; 5-methyl-1,3,4-oxadiazol-2-yl;3-methyl-1,2,4-oxadiazol-5-yl; 1-methyl-1H-tetrazol-5-yl;2-methyl-2H-tetrazol-5-yl; 1H-tetrazol-1-yl; 2H-tetrazol-5-yl;5-methyl-1H-tetrazol-1-yl; or 5-(methoxymethyl)-1H-tetrazol-1-yl.

In certain embodiments of formula I, R⁵ is: 1-methyl-1H-imidazol-2-yl;1-methyl-1H-imidazol-5-yl; 1,3,5-trimethyl-1H-pyrazol-4-yl;1-methyl-1H-pyrazol-5-yl; 1-methyl-1H-pyrazol-4-yl;1,3-dimethyl-1H-pyrazol-4-yl; 1,5-dimethyl-1H-pyrazol-4-yl;5-(dimethylaminocarbonyl)-1-methyl-1H-pyrazol-4-yl;1-(oxetan-3-yl)-1H-pyrazol-4-yl;5-(methoxymethyl)-3-methyl-1H-pyrazol-1-yl;1-methyl-1H-1,2,3-triazol-5-yl; 1H-1,2,4-triazol-1-yl;4-methyl-4H-1,2,4-triazol-3-yl; 5-methyl-1,3,4-oxadiazol-2-yl;3-methyl-1,2,4-oxadiazol-5-yl; 1-methyl-1H-tetrazol-5-yl;2-methyl-2H-tetrazol-5-yl; 1H-tetrazol-1-yl; 2H-tetrazol-5-yl;5-methyl-1H-tetrazol-1-yl; or 5-(methoxymethyl)-1H-tetrazol-1-yl.

In certain embodiments of formula I, R⁵ is:1-methyl-1H-1,2,3-triazol-5-yl; 1H-1,2,4-triazol-1-yl;4-methyl-4H-1,2,4-triazol-3-yl; 5-methyl-1,3,4-oxadiazol-2-yl;3-methyl-1,2,4-oxadiazol-5-yl; 1-methyl-1H-tetrazol-5-yl;2-methyl-2H-tetrazol-5-yl; 1H-tetrazol-1-yl; 2H-tetrazol-5-yl;5-methyl-1H-tetrazol-1-yl; or 5-(methoxymethyl)-1H-tetrazol-1-yl.

In certain embodiments of formula I, R⁵ is: 1-methyl-1H-imidazol-2-yl;or 1-methyl-1H-imidazol-5-yl.

In certain embodiments of formula I, R⁵ is:1,3,5-trimethyl-1H-pyrazol-4-yl; 1-methyl-1H-pyrazol-5-yl;1-methyl-1H-pyrazol-4-yl; 1,3-dimethyl-1H-pyrazol-4-yl;1,5-dimethyl-1H-pyrazol-4-yl;5-(dimethylaminocarbonyl)-1-methyl-1H-pyrazol-4-yl;1-(oxetan-3-yl)-1H-pyrazol-4-yl; or5-(methoxymethyl)-3-methyl-1H-pyrazol-1-yl.

In certain embodiments of formula I, R⁵ is:1-methyl-1H-1,2,3-triazol-5-yl; 1H-1,2,4-triazol-1-yl; or4-methyl-4H-1,2,4-triazol-3-yl.

In certain embodiments of formula I, R⁵ is:5-methyl-1,3,4-oxadiazol-2-yl; or 3-methyl-1,2,4-oxadiazol-5-yl.

In certain embodiments of formula I, R⁵ is: 1-methyl-1H-tetrazol-5-yl;2-methyl-2H-tetrazol-5-yl; 1H-tetrazol-1-yl; 2H-tetrazol-5-yl;5-methyl-1H-tetrazol-1-yl; or 5-(methoxymethyl)-1H-tetrazol-1-yl.

In certain embodiments of formula I, R⁵ is thiazol-5-yl. In certainembodiments of formula I, R⁵ is thiazol-4-yl.

In certain embodiments of formula I, R⁵ is thiazol-5-yl. In certainembodiments of formula I, R⁵ is thiazol-5-yl.

In certain embodiments of formula I, R⁵ is thiazol-5-yl. In certainembodiments of formula I, R⁵ is isoxazol-4-yl.

In certain embodiments of formula I, R⁵ is thiazol-5-yl. In certainembodiments of formula I, R⁵ is isoxazol-4-yl.

In certain embodiments of formula I, R⁵ is thiazol-5-yl.

In certain embodiments of formula I, R⁵ is isoxazol-4-yl.

In certain embodiments of formula I, R⁵ is thiazol-5-yl.

In certain embodiments of formula I, R⁵ is isoxazol-4-yl.

In certain embodiments of formula I, R⁵ is 3,5-dimethylisoxazol-4-yl.

In certain embodiments of formula I, R⁵ is 1-methyl-1H-imidazol-2-yl.

In certain embodiments of formula I, R⁵ is 1-methyl-1H-imidazol-5-yl.

In certain embodiments of formula I, R⁵ is1,3,5-trimethyl-1H-pyrazol-4-yl.

In certain embodiments of formula I, R⁵ is 1-methyl-1H-pyrazol-5-yl.

In certain embodiments of formula I, R⁵ is 1-methyl-1H-pyrazol-4-yl.

In certain embodiments of formula I, R⁵ is 1,3-dimethyl-1H-pyrazol-4-yl.

In certain embodiments of formula I, R⁵ is 1,5-dimethyl-1H-pyrazol-4-yl.

In certain embodiments of formula I, R⁵ is5-(dimethylaminocarbonyl)-1-methyl-1H-pyrazol-4-yl.

In certain embodiments of formula I, R⁵ is1-(oxetan-3-yl)-1H-pyrazol-4-yl.

In certain embodiments of formula I, R⁵ is5-(methoxymethyl)-3-methyl-1H-pyrazol-1-yl.

In certain embodiments of formula I, R⁵ is1-methyl-1H-1,2,3-triazol-5-yl.

In certain embodiments of formula I, R⁵ is 1H-1,2,4-triazol-1-yl.

In certain embodiments of formula I, R⁵ is4-methyl-4H-1,2,4-triazol-3-yl.

In certain embodiments of formula I, R⁵ is5-methyl-1,3,4-oxadiazol-2-yl.

In certain embodiments of formula I, R⁵ is3-methyl-1,2,4-oxadiazol-5-yl.

In certain embodiments of formula I, R⁵ is 1-methyl-1H-tetrazol-5-yl.

In certain embodiments of formula I, R⁵ is 2-methyl-2H-tetrazol-5-yl.

In certain embodiments of formula I, R⁵ is 1H-tetrazol-1-yl.

In certain embodiments of formula I, R⁵ is 2H-tetrazol-5-yl.

In certain embodiments of formula I, R⁵ is 5-methyl-1H-tetrazol-1-yl.

In certain embodiments of formula I, R⁵ is5-(methoxymethyl)-1H-tetrazol-1-yl.

In certain embodiments of formula I, R⁶ is C₁₋₆alkyl.

In certain embodiments of formula I, R⁶ is C₃₋₆cycloalkyl.

In certain embodiments of formula I, R⁶ is C₃₋₆cycloalkyl-C₁₋₆alkyl.

In certain embodiments of formula I, R⁶ is halo.

In certain embodiments of formula I, R⁶ is halo-C₁₋₆alkyl.

In certain embodiments of formula I, R⁶ is C₁₋₆alkoxy.

In certain embodiments of formula I, R⁶ is heterocyclyl.

In certain embodiments of formula I, R⁶ is oxo.

In certain embodiments of formula I, R⁶ is —C(O)—NR^(b)R^(c) whereinR^(b) and R^(c) each independently is hydrogen or —C₁₋₆alkyl.

In certain embodiments of the invention, the subject compounds are offormula II

wherein m, X, R¹, R², R³, R⁴ and R⁵ are as defined herein for formula I.

The invention also provides a method for treating a disease or conditionmediated by or otherwise associated with the LRRK2 receptor, the methodcomprising administering to a subject in need thereof an effectiveamount of a compound of the invention.

The disease may be a neurodegenerative disease such as Parkinson'sdisease, Huntington's disease or Lewie body dementia.

The disease may be a CNS disorder such as Alzheimer's disease and L-Dopainduced dyskinesia.

The disease may be a cancer or proliferative disorder such as kidney,breast, prostate, blood, papillary or lung cancer, acute myelogenousleukemia, or multiple myeloma.

The disease may be an inflammatory disease such as leprosy, Crohn'sdisease, amyotrophic lateral sclerosis, rheumatoid arthritis, andankylosing spondylytis.

The invention also provides a method for enhancing cognitive memory, themethod comprising administering to a subject in need thereof aneffective amount of a compound of the invention.

Representative compounds in accordance with the methods of the inventionare shown in the experimental examples below.

Synthesis

Compounds of the present invention can be made by a variety of methodsdepicted in the illustrative synthetic reaction schemes shown anddescribed below.

The starting materials and reagents used in preparing these compoundsgenerally are either available from commercial suppliers, such asAldrich Chemical Co., or are prepared by methods known to those skilledin the art following procedures set forth in references such as Fieserand Fieser's Reagents for Organic Synthesis; Wiley & Sons: New York,1991, Volumes 1-15; Rodd's Chemistry of Carbon Compounds, ElsevierScience Publishers, 1989, Volumes 1-5 and Supplementals; and OrganicReactions, Wiley & Sons: New York, 1991, Volumes 1-40. The followingsynthetic reaction schemes are merely illustrative of some methods bywhich the compounds of the present invention can be synthesized, andvarious modifications to these synthetic reaction schemes can be madeand will be suggested to one skilled in the art having referred to thedisclosure contained in this application.

The starting materials and the intermediates of the synthetic reactionschemes can be isolated and purified if desired using conventionaltechniques, including but not limited to, filtration, distillation,crystallization, chromatography, and the like. Such materials can becharacterized using conventional means, including physical constants andspectral data.

Unless specified to the contrary, the reactions described herein may beconducted under an inert atmosphere at atmospheric pressure at areaction temperature range of from about −78° C. to about 150° C., forexample, from about 0° C. to about 125° C., or conveniently at aboutroom (or ambient) temperature, e.g., about 20° C.

Scheme A below illustrates one synthetic procedure usable to preparespecific compounds of formula I or formula II, wherein X, m, R¹, R², R³,R⁴ and R⁵ are as defined herein.

In step 1 of Scheme A, dichloropyrimidine compound a is reacted withreagent b to afford pyrimidine compound c. The reaction of step 1 maytake place under polar solvent conditions. In embodiments of theinvention where X is —O— (i.e., reagent b is an alcohol), the reactionof step 1 may be carried out in the presence of base.

In step 2, pyrimidine compound c undergoes reaction with anilinecompound d to provide a phenylaminopyridine compound of formula I inaccordance with the invention. The reaction of step 2 may take place inpolar protic solvent and in the presence of acid such as HCl. Manyaniline compound d are commercially available or can be easily preparedfrom nitrobenzenes as shown in the Examples below.

Many variations on the procedure of Scheme A are possible and willsuggest themselves to those skilled in the art. Specific details forproducing compounds of the invention are described in the Examplesbelow.

Administration and Pharmaceutical Composition

The invention includes pharmaceutical compositions comprising at leastone compound of the present invention, or an individual isomer, racemicor non-racemic mixture of isomers or a pharmaceutically acceptable saltor solvate thereof, together with at least one pharmaceuticallyacceptable carrier, and optionally other therapeutic and/or prophylacticingredients.

In general, the compounds of the invention will be administered in atherapeutically effective amount by any of the accepted modes ofadministration for agents that serve similar utilities. Suitable dosageranges are typically 1-500 mg daily, for example 1-100 mg daily, andmost preferably 1-30 mg daily, depending upon numerous factors such asthe severity of the disease to be treated, the age and relative healthof the subject, the potency of the compound used, the route and form ofadministration, the indication towards which the administration isdirected, and the preferences and experience of the medical practitionerinvolved. One of ordinary skill in the art of treating such diseaseswill be able, without undue experimentation and in reliance uponpersonal knowledge and the disclosure of this application, to ascertaina therapeutically effective amount of the compounds of the presentinvention for a given disease.

Compounds of the invention may be administered as pharmaceuticalformulations including those suitable for oral (including buccal andsub-lingual), rectal, nasal, topical, pulmonary, vaginal, or parenteral(including intramuscular, intraarterial, intrathecal, subcutaneous andintravenous) administration or in a form suitable for administration byinhalation or insufflation. A particular manner of administration isgenerally oral using a convenient daily dosage regimen which can beadjusted according to the degree of affliction.

A compound or compounds of the invention, together with one or moreconventional adjuvants, carriers, or diluents, may be placed into theform of pharmaceutical compositions and unit dosages. The pharmaceuticalcompositions and unit dosage forms may be comprised of conventionalingredients in conventional proportions, with or without additionalactive compounds or principles, and the unit dosage forms may containany suitable effective amount of the active ingredient commensurate withthe intended daily dosage range to be employed. The pharmaceuticalcompositions may be employed as solids, such as tablets or filledcapsules, semisolids, powders, sustained release formulations, orliquids such as solutions, suspensions, emulsions, elixirs, or filledcapsules for oral use; or in the form of suppositories for rectal orvaginal administration; or in the form of sterile injectable solutionsfor parenteral use. Formulations containing about one (1) milligram ofactive ingredient or, more broadly, about 0.01 to about one hundred(100) milligrams, per tablet, are accordingly suitable representativeunit dosage forms.

The compounds of the invention may be formulated in a wide variety oforal administration dosage forms. The pharmaceutical compositions anddosage forms may comprise a compound or compounds of the presentinvention or pharmaceutically acceptable salts thereof as the activecomponent. The pharmaceutically acceptable carriers may be either solidor liquid. Solid form preparations include powders, tablets, pills,capsules, cachets, suppositories, and dispersible granules. A solidcarrier may be one or more substances which may also act as diluents,flavouring agents, solubilizers, lubricants, suspending agents, binders,preservatives, tablet disintegrating agents, or an encapsulatingmaterial. In powders, the carrier generally is a finely divided solidwhich is a mixture with the finely divided active component. In tablets,the active component generally is mixed with the carrier having thenecessary binding capacity in suitable proportions and compacted in theshape and size desired. The powders and tablets may contain from aboutone (1) to about seventy (70) percent of the active compound. Suitablecarriers include but are not limited to magnesium carbonate, magnesiumstearate, talc, sugar, lactose, pectin, dextrin, starch, gelatine,tragacanth, methylcellulose, sodium carboxymethylcellulose, a lowmelting wax, cocoa butter, and the like. The term “preparation” isintended to include the formulation of the active compound withencapsulating material as carrier, providing a capsule in which theactive component, with or without carriers, is surrounded by a carrier,which is in association with it. Similarly, cachets and lozenges areincluded. Tablets, powders, capsules, pills, cachets, and lozenges maybe as solid forms suitable for oral administration.

Other forms suitable for oral administration include liquid formpreparations including emulsions, syrups, elixirs, aqueous solutions,aqueous suspensions, or solid form preparations which are intended to beconverted shortly before use to liquid form preparations. Emulsions maybe prepared in solutions, for example, in aqueous propylene glycolsolutions or may contain emulsifying agents, for example, such aslecithin, sorbitan monooleate, or acacia. Aqueous solutions can beprepared by dissolving the active component in water and adding suitablecolorants, flavors, stabilizers, and thickening agents. Aqueoussuspensions can be prepared by dispersing the finely divided activecomponent in water with viscous material, such as natural or syntheticgums, resins, methylcellulose, sodium carboxymethylcellulose, and otherwell known suspending agents. Solid form preparations include solutions,suspensions, and emulsions, and may contain, in addition to the activecomponent, colorants, flavors, stabilizers, buffers, artificial andnatural sweeteners, dispersants, thickeners, solubilizing agents, andthe like.

The compounds of the invention may be formulated for parenteraladministration (e.g., by injection, for example bolus injection orcontinuous infusion) and may be presented in unit dose form in ampoules,pre-filled syringes, small volume infusion or in multi-dose containerswith an added preservative. The compositions may take such forms assuspensions, solutions, or emulsions in oily or aqueous vehicles, forexample solutions in aqueous polyethylene glycol. Examples of oily ornonaqueous carriers, diluents, solvents or vehicles include propyleneglycol, polyethylene glycol, vegetable oils (e.g., olive oil), andinjectable organic esters (e.g., ethyl oleate), and may containformulatory agents such as preserving, wetting, emulsifying orsuspending, stabilizing and/or dispersing agents. Alternatively, theactive ingredient may be in powder form, obtained by aseptic isolationof sterile solid or by lyophilization from solution for constitutionbefore use with a suitable vehicle, e.g., sterile, pyrogen-free water.

The compounds of the invention may be formulated for topicaladministration to the epidermis as ointments, creams or lotions, or as atransdermal patch. Ointments and creams may, for example, be formulatedwith an aqueous or oily base with the addition of suitable thickeningand/or gelling agents. Lotions may be formulated with an aqueous or oilybase and will in general also containing one or more emulsifying agents,stabilizing agents, dispersing agents, suspending agents, thickeningagents, or coloring agents. Formulations suitable for topicaladministration in the mouth include lozenges comprising active agents ina flavored base, usually sucrose and acacia or tragacanth; pastillescomprising the active ingredient in an inert base such as gelatine andglycerine or sucrose and acacia; and mouthwashes comprising the activeingredient in a suitable liquid carrier.

The compounds of the invention may be formulated for administration assuppositories. A low melting wax, such as a mixture of fatty acidglycerides or cocoa butter is first melted and the active component isdispersed homogeneously, for example, by stirring. The moltenhomogeneous mixture is then poured into convenient sized molds, allowedto cool, and to solidify.

The compounds of the invention may be formulated for vaginaladministration. Pessaries, tampons, creams, gels, pastes, foams orsprays containing in addition to the active ingredient such carriers asare known in the art to be appropriate.

The subject compounds may be formulated for nasal administration. Thesolutions or suspensions are applied directly to the nasal cavity byconventional means, for example, with a dropper, pipette or spray. Theformulations may be provided in a single or multidose form. In thelatter case of a dropper or pipette, this may be achieved by the patientadministering an appropriate, predetermined volume of the solution orsuspension. In the case of a spray, this may be achieved for example bymeans of a metering atomizing spray pump.

The compounds of the invention may be formulated for aerosoladministration, particularly to the respiratory tract and includingintranasal administration. The compound will generally have a smallparticle size for example of the order of five (5) microns or less. Sucha particle size may be obtained by means known in the art, for exampleby micronization. The active ingredient is provided in a pressurizedpack with a suitable propellant such as a chlorofluorocarbon (CFC), forexample, dichlorodifluoromethane, trichlorofluoromethane, ordichlorotetrafluoroethane, or carbon dioxide or other suitable gas. Theaerosol may conveniently also contain a surfactant such as lecithin. Thedose of drug may be controlled by a metered valve. Alternatively theactive ingredients may be provided in a form of a dry powder, forexample a powder mix of the compound in a suitable powder base such aslactose, starch, starch derivatives such as hydroxypropylmethylcellulose and polyvinylpyrrolidine (PVP). The powder carrier will form agel in the nasal cavity. The powder composition may be presented in unitdose form for example in capsules or cartridges of e.g., gelatine orblister packs from which the powder may be administered by means of aninhaler.

When desired, formulations can be prepared with enteric coatings adaptedfor sustained or controlled release administration of the activeingredient. For example, the compounds of the present invention can beformulated in transdermal or subcutaneous drug delivery devices. Thesedelivery systems are advantageous when sustained release of the compoundis necessary and when patient compliance with a treatment regimen iscrucial. Compounds in transdermal delivery systems are frequentlyattached to an skin-adhesive solid support. The compound of interest canalso be combined with a penetration enhancer, e.g., Azone(1-dodecylazacycloheptan-2-one). Sustained release delivery systems areinserted subcutaneously into the subdermal layer by surgery orinjection. The subdermal implants encapsulate the compound in a lipidsoluble membrane, e.g., silicone rubber, or a biodegradable polymer,e.g., polylactic acid.

The pharmaceutical preparations may be in unit dosage forms. In suchform, the preparation is subdivided into unit doses containingappropriate quantities of the active component. The unit dosage form canbe a packaged preparation, the package containing discrete quantities ofpreparation, such as packeted tablets, capsules, and powders in vials orampoules. Also, the unit dosage form can be a capsule, tablet, cachet,or lozenge itself, or it can be the appropriate number of any of thesein packaged form.

Other suitable pharmaceutical carriers and their formulations aredescribed in Remington: The Science and Practice of Pharmacy 1995,edited by E. W. Martin, Mack Publishing Company, 19th edition, Easton,Pa. Representative pharmaceutical formulations containing a compound ofthe present invention are described below.

Utility

The compounds of the invention are useful for treatment ofLRRK2-mediated diseases or conditions, including neurodegenerativediseases such as Parkinson's disease, Lewy body dementia andHuntington's disease, and for enhancement of cognitive memory generallyin subjects in need thereof.

EXAMPLES

The following preparations and examples are given to enable thoseskilled in the art to more clearly understand and to practice thepresent invention. They should not be considered as limiting the scopeof the invention, but merely as being illustrative and representativethereof.

Unless otherwise stated, all temperatures including melting points(i.e., MP) are in degrees celsius (° C.). It should be appreciated thatthe reaction which produces the indicated and/or the desired product maynot necessarily result directly from the combination of two reagentswhich were initially added, i.e., there may be one or more intermediateswhich are produced in the mixture which ultimately leads to theformation of the indicated and/or the desired product. The followingabbreviations may be used in the Preparations and Examples.

LIST OF ABBREVIATIONS

-   AcOH Acetic acid-   AIBN 2,2′-Azobis(2-methylpropionitrile)-   Atm. Atmosphere-   (BOC)₂O di-tent-Butyl dicarbonate-   DavePhos 2-Dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl-   DCM Dichloromethane/Methylene chloride-   DIAD Diisopropyl azodicarboxylate-   DIPEA Diisopropylethylamine-   DMAP 4-Dimethylaminopyridine-   DME 1,2-Dimethoxyethane-   DMF N,N-Dimethylformamide-   DMSO Dimethyl sulfoxide-   DPPF 1,1′-Bis(diphenylphosphino)ferrocene-   Et₂O Diethyl ether-   EtOH Ethanol/Ethyl alcohol-   EtOAc Ethyl acetate-   HATU 2-(1H-7-Azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium    hexafluorophosphate Methanaminium-   HBTU O-Benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium    hexafluorophosphate-   HOBT 1-Hydroxybenzotriazole-   HPLC High pressure liquid chromatography-   RP HPLC Reverse phase high pressure liquid chromatography-   i-PrOH Isopropanol/isopropyl alcohol-   LCMS Liquid Chromatograph/Mass Spectroscopy-   MeOH Methanol/Methyl alcohol-   MW Microwaves-   NBS N-Bromosuccinimide-   NMP 1-Methyl-2-pyrrolidinone-   PSI Pound per square inch-   RT Room temperature-   TBDMS tert-Butyldimethylsilyl-   TFA Trifluoroacetic acid-   THF Tetrahydrofuran-   TLC Thin layer chromatography

Preparation 1: 2-chloro-5-fluoro-N-methylpyrimidin-4-amine

To a 250 mL round bottom flask equipped with a stir bar was added 9.0 g5-fluoro-2,4-dichloro-pyrimidine, 40 mL methanol and 15 mL of 8Mmethylamine in ethanol. The reaction heated up (mild exo-therm) and wasallowed to stir at room temperature for ˜30 minutes. A check by TLC (1:1EtOAc:heptane) and LCMS showed complete reaction. The reaction wasconcentrated down to give 9.77 g crude material which was purified on asilica column running a gradient of 1% to 10% MeOH in DCM over 35minutes to give 6.77 g pure 2-chloro-5-fluoro-N-methylpyrimidin-4-amine.

The same method was used to make the compounds shown in Table 1 below,using the appropriate commercially available substituted2,4-dichloro-pyrimidines and amines.

TABLE 1  1 2-chloro-5-chloro-N- methylpyrimidin-4- amine

 2 2-chloro-5-bromo-N- methylpyrimidin-4- amine

 3 2-chloro-5-trifluoromethyl-N- methylpyrimidin-4-amine

 6 2-chloro-5-methoxy-N- methylpyrimidin-4- amine

 8 2-chloro-5-fluoro-N,N- dimethylpyrimidin- 4-amine

 9 2-chloro-5-chloro-N- ethylpyrimidin-4- amine

10 2-chloro-5-chloro-N- propylpyrimidin-4- amine

11 2-chloro-5-chloro-N- isopropylpyrimidin-4- amine

12 2-chloro-5-chloro-N- isobutylpyrimidin-4- amine

13 4-(2,5-dichloropyrimidin- 4-yl)morpholine

14 2,5-dichloropyrimidin-4-amine

15 2,5-dichloro-N,N- dimethylpyrimidin-4- amine

16 4-(azetidin-1-yl)-2,5- dichloropyrimidine

17 2,5-dichloro-4-(pyrrolidin- 1-yl)pyrimidine

18 2,5-dichloro-4-(piperidin- 1-yl)pyrimidine

19 2,5-dichloro-4-(2- (methoxymethyl)piperidin- 1-yl)pyrimidine

20 2,5-dichloro-4-(4- (methoxymethyl)piperidin- 1-yl)pyrimidine

21 2,5-dichloro-N- (cyclopropylmethyl) pyrimidin-4-amine

22 2,5-dichloro-N- (cyclobutylmethyl) pyrimidin-4-amine

23 2,5-dichloro-N- (cyclopentylmethyl) pyrimidin-4-amine

24 2-chloro-N- methylpyrimidin-4-amine

25 2,5-dichloro-N-(2- methoxyethyl)pyrimidin- 4-amine

Preparation 2: 2,5-dichloro-4-methoxypyrimidine

To a 250 mL round bottom flask equipped with a stir bar was added 1 g5-chloro-2,4-dichloro-pyrimidine, and 15 mL of diethyl ether. Themixture was cooled to 0° C. in an ice bath and then 1 equivalent ofsodium methoxide in methanol (prepared from reacting 120 mg of sodiumwith 4 mL of methanol at room temperature) was slowly added. Thereaction was stirred over night at room temperature and checked by LCMS.The white precipitate was filtered and the solid washed with coldmethanol. After drying, 0.98 g of pure 2,5-dichloro-4-methoxypyrimidinewas obtained and this material was used without further purification.

The same method was used to make the compounds shown in Table 2 below,using the appropriate commercially available alcohols and theappropriately substituted 2,4-dichloro-pyrimidines.

TABLE 2 1 2,5-dichloro-4-ethoxypyrimidine

2 2,5-dichloro-4-propoxypyrimidine

3 2,5-dichloro-4-isoprpoxypyrimidine

6 5-bromo-2-chloro-4- methoxypyrimidine

7 2-chloro-5-iodo-4- methoxypyrimidine

Example 1N²-(2-Chloro-4-(2H-tetrazol-5-yl)phenyl)-N⁴-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamineStep 1:3-Chloro-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)benzonitrile

A mixture of 2-chloro-N-methyl-5-(trifluoromethyl)pyrimidin-4-amine (211mg, 1 mmol), 4-amino-3-chlorobenzonitrile (305 mg, 2 mmol), cesiumcarbonate (0.65 g, 2 mmol), XantPhos (17 mg, 0.03 mmol) and Pd₂(dba)₃ (5mg, 0.02 mmol) in dioxane (3 mL) was sonnicated in an ultrasonic bathfor 1 min. The mixture was then degassed under a stream of nitrogen for5 min. The tube was sealed and the reaction was heated at 100° C. for 18h. The reaction mixture was cooled and diluted with ethyl acetate (15mL). The organic layer was washed with water (2×20 mL) and the combinedaqueous extracts were further washed with ethyl acetate (2×15 mL). Thecombined organics were passed through a phase separation cartridge andthe solvent removed under reduced pressure. Purification of the residuevia silica gel column chromatography (0-100% ethyl acetate/isohexane)gave3-chloro-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)benzonitrileas a white solid (140 mg, 45%). ¹H NMR (400 MHz, CDCl₃): δ 8.85 (d,J=8.8, 1H); 8.23 (d, J=1.1, 1H); 7.80 (s, 1H); 7.68 (d, J=1.9, 1H);7.58-7.53 (m, 1H); 5.32 (s br, 1H); 3.11 (d, J=4.7, 3H).

Step 2:N²-(2-Chloro-4-(2H-tetrazol-5-yl)phenyl)-N⁴-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine

To a solution of3-chloro-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)benzonitrile(135 mg, 6.41 mmol) in DMF (2 mL) was added sodium azide (80 mg, 1.24mmol) and ammonium chloride (66 mg, 1.24 mmol). The mixture was heatedat 125° C. for 18 h. The mixture was cooled, filtered and the solidwashed with ethyl acetate. The filtrated was concentrated under reducedpressure and the crude residue was diluted with water (5 mL) and diethylether (5 mL). A precipitate formed which was filtered and washed withfurther portions of water and diethyl ether. The solid was co-evaporatedwith dichloromethane and methanol and then dried in a vacuum oven toyieldN²-(2-chloro-4-(2H-tetrazol-5-yl)phenyl)-N⁴-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine(130 mg, 85%). LCMS (ESCI_Formic_MeCN): [MH⁺]=371 at 3.11 min. ¹H NMR(400 MHz, DMSO): δ 8.94 (s, 1H); 8.26-8.19 (m, 2H); 8.14 (d, J=2.0, 1H);8.03-7.96 (m, 1H); 7.30-7.22 (m, 1H); 2.89 (t, J=4.4, 3H).

Examples 2 and 3N²-(2-Chloro-4-(2-methyl-2H-tetrazol-5-yl)phenyl)-N⁴-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamineandN²-(2-chloro-4-(1-methyl-1H-tetrazol-5-yl)phenyl)-N⁴-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine

A mixture ofN²-(2-chloro-4-(2H-tetrazol-5-yl)phenyl)-N⁴-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine(80 mg, 0.22 mmol), K₂CO₃ (45 mg, 0.32 mmol) and methyl iodide (15 uL,0.24 mmol) in acetone (2 mL) was heated at 40° C. for 1 h. The mixturewas cooled and filtered. The filtrate was concentrated under reducedpressure and the crude residue purified via silica gel columnchromatography (0-100% ethyl acetate/isohexane) to giveN²-(2-chloro-4-(2-methyl-2H-tetrazol-5-yl)phenyl)-N⁴-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine(58 mg, 70%). LCMS (10 cm_ESCI_Formic_MeCN): [MH⁺]=385 at 4.31 min. ¹HNMR (400 MHz, CDCl₃): δ 8.76 (d, J=8.7, 1H); 8.23-8.19 (m, 2H); 8.05(dd, J=8.7, 2.0, 1H); 7.72 (s, 1H); 5.29 (s, 1H); 4.40 (s, 3H); 3.12 (d,J=4.7, 3H).

IsomerN²-(2-chloro-4-(1-methyl-1H-tetrazol-5-yl)phenyl)-N⁴-methyl-5-(trifluoromethyl)pyrimidine-2,4-diaminewas also isolated (10 mg, 12%). LCMS (10 cm_ESCI_Formic_MeCN): [MH⁺]=385at 3.8 min. ¹H NMR (400 MHz, CDCl₃): δ 8.90 (d, J=8.7, 1H); 8.24 (s,1H); 7.86 (d, J=2.1, 1H); 7.79 (s, 1H); 7.68 (dd, J=8.8, 2.1, 1H); 5.33(s, 1H); 4.22 (s, 3H); 3.13 (d, J=4.7, 3H).

Example 4N²-(2-Methoxy-4-(1H-1,2,4-triazol-1-yl)phenyl)-N⁴-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamineStep 1: 2-Methoxy-4-(1H-1,2,4-triazol-1-yl)aniline

A mixture of 4-bromo-2-methoxyaniline (208 mg, 1.03 mmol),1,2,4-triazole (80 mg, 1.13 mmol), Cs₂CO₃ (0.67 g, 2.06 mmol) and CuI(20 mg, 0.103 mmol) in DMF was heated at 110° C. for 20 h. Furtherportions of 1,2,4-triazole (0.1 g, 1.44 mmol), Cs₂CO₃ (0.67 g, 2.06mmol) and CuI (0.1 g, 0.52 mmol) were added and the mixture was heated afurther 72 h at 110° C. The mixture was cooled, diluted with ethylacetate (20 mL) and washed with water (2×20 mL). The combined aqueouswashes were re-extracted with ethyl acetate (20 mL). The combinedorganics were passed through a phase separation cartridge and thesolvent removed under reduced pressure. Purification of the residue viasilica gel column chromatography (0-100% ethyl acetate/isohexane) gave2-methoxy-4-(1H-1,2,4-triazol-1-yl)aniline as a light red solid (92 mg,47%). ¹H NMR (400 MHz, CDCl₃): δ 8.41 (s, 1H); 8.05 (s, 1H); 7.11 (d,J=2.3, 1H); 6.99 (dd, J=8.3, 2.3, 1H); 6.74 (d, J=8.3, 1H); 3.97 (s,2H); 3.92 (s, 3H).

Step 2:N²-(2-Methoxy-4-(1H-1,2,4-triazol-1-yl)phenyl)-N⁴-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine

A mixture of 2-chloro-N-methyl-5-(trifluoromethyl)pyrimidin-4-amine (80mg, 0.38 mmol), 2-methoxy-4-(1H-1,2,4-triazol-1-yl)aniline (72 mg, 0.38mmol) and p-toluene sulphonic acid (72 mg, 0.38 mmol) in dioxane (2 mL)was heated at 100° C. for 1 h. The mixture was cooled and filtered. Thesolid was partitioned between dichloromethane (10 mL) and saturatedaqueous NaHCO₃ (10 mL) and the product was extracted intodichloromethane (3×10 mL). The combined organics were passed through aphase separation cartridge and the solvent removed under reducedpressure. Purification of the residue via silica gel columnchromatography (0-100% ethyl acetate/isohexane) afforded a residue thatwas triturated with methanol/diethyl ether yieldingN²-(2-methoxy-4-(1H-1,2,4-triazol-1-yl)phenyl)-N⁴-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamineas a white solid (34.5 mg, 25%). LCMS (10 cm_ESCI_Formic_MeCN):[MH⁺]=366 at 3.13 min. ¹H NMR (400 MHz, DMSO): δ 9.29 (s, 1H); 8.33 (d,J=8.7, 1H); 8.24-8.15 (m, 3H); 7.53 (d, J=2.4, 1H); 7.45 (dd, J=8.7,2.4, 1H); 7.23 (d, J=5.2, 1H); 3.97 (s, 3H); 2.92 (d, J=4.4, 3H).

Example 5N²-(2-Methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-N⁴-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamineStep 1:N²-(4-Bromo-2-methoxyphenyl)-N⁴-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine

A mixture of 2-chloro-N-methyl-5-(trifluoromethyl)pyrimidin-4-amine (0.5g, 2.36 mmol), 4-bromo-2-methoxyaniline (0.72 g, 0.38 mmol) andp-toluene sulphonic acid (0.49 g, 2.6 mmol) in dioxane (10 mL) washeated at 100° C. for 2 h. The mixture was cooled, filtered and thesolid washed with dioxane. The solid was dried in a vacuum oven to givecrudeN²-(4-bromo-2-methoxyphenyl)-N⁴-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine(1.31 g) which was used in the next step without any furtherpurification.

Step 2:N²-(2-Methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-N⁴-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine

A mixture ofN²-(4-bromo-2-methoxyphenyl)-N⁴-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine(0.365 g, 1 mmol), Pd(PPh₃)₄ (115 mg, 0.1 mmol), K₂CO₃ (0.415 g, 3 mmol)and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(0.415 g, 2 mmol) in dioxane (10 mL) and water (1.25 mL) was degassedunder a stream of nitrogen for 10 min. The reaction tube was sealed andthe mixture irradiated in the microwave at 100° C. for 20 min. Themixture was cooled and concentrated under reduced pressure. The residuewas partitioned between ethyl acetate (20 mL) and water (20 mL) and theproduct extracted into ethyl acetate (2×20 mL). The combined organicswere passed through a phase separation cartridge and the solvent removedunder reduced pressure. Purification of the residue via silica gelcolumn chromatography (0-100% ethyl acetate/isohexane) afforded aresidue that was triturated with diethyl ether yieldingN²-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-N⁴-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamineas an off-white solid (94 mg, 25%). LCMS (10 cm_ESCI_Formic_MeCN):[MH⁺]=379 at 3.11 min. ¹H NMR (400 MHz, CDCl): δ 8.49 (d, J=8.4, 1H);8.17 (s, 1H); 7.76-7.68 (m, 2H); 7.58 (s, 1H); 7.10 (dd, J=8.4, 1.9,1H); 6.98 (d, J=1.9, 1H); 5.20 (s, 1H); 3.95 (s, 6H); 3.12 (d, J=4.7,3H).

Example 6N²-(5-Fluoro-2-methoxy-4-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl)-N⁴-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamineStep 1:2-Fluoro-5-methoxy-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)benzoicacid

2-Fluoro-5-methoxy-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)benzoicacid was prepared by the procedure described in Example 5, step 1 using4-amino-2-fluoro-5-methoxybenzoic acid (1.35 g, quant.).

Step 2:N²-(5-Fluoro-2-methoxy-4-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl)-N⁴-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine

A mixture of2-fluoro-5-methoxy-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)benzoicacid (0.1 g, 0.28 mmol), HATU (127 mg, 0.33 mmol) and DIPEA (60 uL, 6.33mmol) in DMF (2 mL) was stirred at room temperature for 5 min.N-Hydroxyacetimidamide (25 mg, 0.33 mmol) was added and the mixture wasstirred at room temperature for 30 min followed by 100° C. for 18 h.Additional HATU (127 mg, 0.33 mmol), DIPEA (60 uL, 6.33 mmol) andN-hydroxyacetimidamide (25 mg, 0.33 mmol) were added and the reactionwas heated at 100° C. for a further 8 h. The mixture was cooled anddiluted with ethyl acetate (10 mL). The organic layer was washed withsaturated aqueous NaHCO₃ (2×5 mL) and the combined aqueous washes wereextracted with further ethyl acetate (2×10 mL). The combined organicswere passed through a phase separation cartridge and the solvent removedunder reduced pressure. Purification of the residue via silica gelcolumn chromatography (0-100% ethyl acetate/isohexane) affordedN²-(5-fluoro-2-methoxy-4-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl)-N⁴-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamineas a white solid (16 mg, 15%). LCMS (10 cm_ESCI_Formic_MeCN): [MH⁺]=399at 4.51 min. ¹H NMR (400 MHz, CDCl₃): δ 8.67 (d, J=13, 1H); 8.23 (s,1H); 8.01 (s, 1H); 7.48 (d, J=6.1, 1H); 5.33 (s, 1H); 4.00 (s, 3H); 3.16(d, J=4.7, 3H); 2.51-2.44 (m, 3H).

Example 7N²-(2-chloro-5-methoxy-4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)-N⁴-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamineStep 1:5-Chloro-2-methoxy-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)benzoicacid

5-Chloro-2-methoxy-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)benzoicacid was prepared by the procedure described in Example 5, step 1 using4-amino-5-chloro-2-methoxybenzoic acid (1.01 g, quant.).

Step 2:N′-Acetoyl-5-chloro-2-methoxy-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)benzohydrazide

A suspension of5-chloro-2-methoxy-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)benzoicacid (144 mg, 50% pure material, 0.19 mmol), HATU (85 mg, 0.22 mmol),acetic hydrazide (16 mg, 0.22 mmol) and DIPEA (81 uL, 0.46 mmol) indichloromethane (4 mL) was stirred at room temperature for 18 h. Themixture was diluted with dichloromethane (10 mL) and washed withsaturated aqueous NaHCO₃ solution (10 mL). A solid persisted in theaqueous layer; this was filtered, washed with water and then suspendedin methanol. The solid was collected by filtration and dried in a vacuumoven to affordN′-acetoyl-5-chloro-2-methoxy-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)benzohydrazideas a white solid (68 mg, 85%). This was taken through to the next stepwithout further purification.

Step 3:N²-(2-Chloro-5-methoxy-4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)-N⁴-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine

A mixture ofN′-acetoyl-5-chloro-2-methoxy-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)benzohydrazide(68 mg, 0.16 mmol), and1-methoxy-N-triethylammoniosulfonyl-methanimidate (Burgess reagent) (75mg, 0.32 mmol) in THF (4 mL) was irradiated in the microwave at 150° C.for 30 min. An additional portion of Burgess reagent (75 mg, 0.32 mmol)was added and the reaction was irradiated a further 30 min at 150° C. inthe microwave. The reaction mixture was concentrated and the cruderesidue purified via silica gel column chromatography (0-100% ethylacetate/isohexane) to afford a residue that was triturated with diethylether/methanol yieldingN²-(2-chloro-5-methoxy-4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)-N⁴-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamineas a white solid (28 mg, 43%). HPLC (15 cm_Formic_Ascentis_HPLC_CH₃CN):at 9.15 min. LCMS (10 cm_ESCI_Formic_MeCN): [MH⁺]=415 at 4.00 min. ¹HNMR (400 MHz, CDCl): δ 8.62 (s, 1H); 8.25 (s, 1H); 7.95 (s, 1H); 7.80(s, 1H); 5.34 (s, 1H); 4.01 (s, 3H); 3.15 (d, J=4.7, 3H); 2.61 (s, 3H).

Example 8N²-(2-methoxy-4-(1-methyl-1H-imidazol-5-yl)phenyl)-N⁴-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine

A mixture ofN²-(4-bromo-2-methoxyphenyl)-N⁴-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine(0.151 g, 0.4 mmol), Pd(dppf)Cl₂ (33 mg, 0.04 mmol) and1-methyl-5-(tributylstannyl)-1H-imidazole (297 mg, 0.8 mmol) in dioxane(5 mL) was degassed under a stream of nitrogen for 10 min. The reactiontube was sealed and heated at 100° C. during 18 hours. The mixture wascooled and concentrated under reduced pressure. The residue waspartitioned between ethyl acetate (20 mL) and water (20 mL) and theproduct extracted into ethyl acetate (2×20 mL). The combined organicswere passed through a phase separation cartridge and the solvent removedunder reduced pressure. Purification of the residue via preparative HPLCaffordedN²-(2-methoxy-4-(1-methyl-1H-imidazol-5-yl)phenyl)-N⁴-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamineas a beige solid (64 mg, 42%). LCMS (10 cm_ESCI_Bicarb_MeCN): [MH⁺]=379at 3.59 min. ¹H NMR (400 MHz, DMSO): δ 8.33 (d, J=8.3, 1H); 8.21 (s,1H); 8.10 (s, 1H); 7.72 (s, 1H); 7.23 (d, J=5.2, 1H); 7.16-7.07 (m, 3H);3.95 (s, 3H); 3.74 (s, 3H); 2.96 (d, J=4.3, 3H).

Example 9N²-(4-methoxy-6-(thiazol-5-yl)pyridin-3-yl)-N⁴-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamineStep 1: 6-Chloro-4-methoxypyridin-3-amine

A mixture of 2-chloro-4-methoxy-5-nitropyridine (208 mg, 1.10 mmol),ammonium chloride (295 mg, 5.52 mmol) and iron powder (246 mg, 4.41mmol) in ethanol (5 mL) and water (0.5 mL) was heated at 80° C. for 18h. The mixture was cooled and filtered through a Celite cartridge andwashed through with methanol. The combined filtrate and washing wasevaporated, and the residue partitioned between DCM (10 mL) and water(10 mL), the organic phase was washed further with water (10 mL), andthe aqueous washes were combined and extracted with DCM (3×5 mL). Theorganic extracts were combined and filtered through a hydrophobic frit,and the solvent was removed by evaporation to give the product as anoff-white solid (155 mg, 89%). ¹H NMR (400 MHz, CDCl₃): δ 7.73 (s, 1H);6.71 (s, 1H); 3.90 (s, 3H); 3.71 (s, 2H).

Step 2:N²-(6-Chloro-4-methoxypyridin-3-yl)-N⁴-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine

A mixture of 2-chloro-N-methyl-5-(trifluoromethyl)pyrimidin-4-amine (211mg, 1 mmol), 6-chloro-4-methoxypyridin-3-amine (150 mg, 0.95 mmol) andpara-toluenesulphonic acid (190 mg, 1 mmol) in 1,4-dioxane (2 mL) washeated at 100° C. for 1 h. The mixture was cooled and filtered, thesolid was washed with dioxane and dried in vacuo to give the product asa cream coloured solid (436 mg, >100%). ¹H NMR (400 MHz, DMSO): δ 9.82(s, 1H); 8.76 (s, 1H); 8.44 (s, 2H); 7.38 (s, 1H); 4.00 (s, 3H);2.99-2.92 (m, 3H).

Step 3:N²-(4-Methoxy-6-(thiazol-5-yl)pyridin-3-yl)-N⁴-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine

N²-(4-Methoxy-6-(thiazol-5-yl)pyridin-3-yl)-N⁴-methyl-5-(trifluoromethyl)pyrimidine-2,4-diaminewas prepared by the procedure described in Example 7, usingN²-(6-chloro-4-methoxypyridin-3-yl)-N⁴-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamineand 5-(tributylstannyl)thiazole. LCMS (10 cm_ESCI_Formic_MeCN):[MH⁺]=383 at 2.60 min. ¹H NMR δ (ppm) (CDCl₃): 9.65 (1H, s), 8.9 (1H, d,J=2.1), 8.2 (1H, d, J=1.1), 8.1 (1H, d, J=2.1), 7.75 (1H, s), 7.55 (1H,s), 5.27 (1H, s), 4.1 (3H, s), 3.2 (3H, d, J=4.7).

Example 105-Chloro-N²-(2-methoxy-4-(1-methyl-1H-tetrazol-5-yl)phenyl)-N⁴-methylpyrimidine-2,4-diamineStep 1: 4-Amino-3-methoxy-N-methylbenzamide

4-Amino-3-methoxy-N-methylbenzamide was prepared by the proceduredescribed in Example 7 using 4-amino-3-methoxybenzoic acid andmethylamine hydrochloride.

Step 2:4-(5-Chloro-4-(methylamino)pyrimidin-2-ylamino)-3-methoxy-N-methylbenzamide

4-(5-Chloro-4-(methylamino)pyrimidin-2-ylamino)-3-methoxy-N-methylbenzamidewas prepared by the procedure described in Example 7 using4-amino-3-methoxy-N-methylbenzamide and2,5-dichloro-N-methylpyrimidin-4-amine. ¹H NMR δ (ppm) (CDCl₃): 8.58(1H, d, J=8.4), 7.95-7.92 (1H, m), 7.70 (1H, s), 7.45 (1H, d, J=1.9),6.09 (1H, s), 5.30 (1H, s), 4.03-3.95 (3H, m), 3.15-3.09 (3H, m), 3.02(3H, t, J=4.8).

Step 3:5-Chloro-N²-(2-methoxy-4-(1-methyl-1H-tetrazol-5-yl)phenyl)-N⁴-methylpyrimidine-2,4-diamine

A mixture of4-(5-chloro-4-(methylamino)pyrimidin-2-ylamino)-3-methoxy-N-methylbenzamide(112 mg, 0.35 mmol) and 2-pyridyl diphenylphosphine (373 mg, 1.42 mmol)was flushed with N₂ for 10 min Anhydrous THF (2 mL) was added followedby dropwise addition of diisopropyl azodicarboxylate (0.28 mL, 1.42mmol). Diphenylphosphoryl azide (0.31 mL, 1.42 mmol) was added dropwiseover 5 min. The mixture was heated at 45° C. under N₂ for 18 h. Themixture was diluted with ethyl acetate (20 mL) and washed with saturatedsodium hydrogen carbonate solution (2×10 mL). The combined aqueouswashes were back-extracted with ethyl acetate (10 mL), and the combinedorganic extracts filtered through a hydrophobic frit and evaporated.Purification of the residue via silica gel column chromatography (0-100%ethyl acetate/isohexane) followed by trituration with diethyl ether gave5-chloro-N²-(2-methoxy-4-(1-methyl-1H-tetrazol-5-yl)phenyl)-N⁴-methylpyrimidine-2,4-diamineas a white solid (45 mg, 38%). LCMS (10 cm_ESCI_Bicarb_MeCN): [MH⁺]=347at 2.67 min. ¹H NMR (400 MHz, CDCl₃): δ 8.76 (d, J=8.5, 1H); 7.96 (s,1H); 7.75 (s, 1H); 7.40 (d, J=1.9, 1H); 7.3 (d, J=2.0, 1H); 5.35 (s,1H); 4.21 (s, 3H); 4.00 (s, 3H); 3.13 (d, J=4.9, 3H).

Example 11N²-(2-Chloro-5-methoxy-4-(1-methyl-1H-1,2,3-triazol-5-yl)phenyl)-N⁴-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine

A mixture ofN²-(4-bromo-2-chloro-5-methoxyphenyl)-N⁴-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine(50 mg, 0.12 mmol), 1-methyl-5-(tributylstannyl)-1H-1,2,3-triazole (68mg, 0.18 mmol) and Pd(dppf)₂Cl₂ (10 mg, 0.012 mmol) in dioxane (4 mL)was degassed under a stream of nitrogen for 10 min. The reaction mixturewas heated to 100° C. for 18 h. Further amounts of1-methyl-5-(tributylstannyl)-1H-1,2,3-triazole (68 mg, 0.18 mmol) andPd(dppf)₂Cl₂ (10 mg, 0.012 mmol) were added and the mixture maintainedat 100° C. for another 24 h, after which further amounts of1-methyl-5-(tributylstannyl)-1H-1,2,3-triazole (68 mg, 0.18 mmol) andPd(dppf)₂Cl₂ (10 mg, 0.012 mmol) were added. The mixture was maintainedat 100° C. for another 48 h. The mixture was cooled and concentrated todryness under vacuum, and the residue partitioned between DCM and water.The separated organic phase was concentrated to dryness under vacuum andthe residue purified by RP-HPLC; the product was isolated as a creamsolid (22 mg, 44%). LCMS (ESCI_Formic_MeCN): [MH⁺]=414 at 3.45 min. ¹HNMR δ (DMSO-d6): 8.58 (s, 1H); 8.16 (s, 1H); 7.98 (s, 1H); 7.71 (s, 1H);7.42 (s, 1H); 7.24 (d, J=5.1, 1H); 3.82 (s, 3H); 3.76 (s, 3H); 2.87 (d,J=4.4, 3H).

The compounds in the above Examples, as well as additional compoundsmade using the same procedures, are shown in Table 3 below together withLRRK2 Ki values (micromolar).

TABLE 3 Structure Name K_(i)  1

N2-(2-chloro-4-(2H- tetrazol-5-yl)phenyl)-N4- methyl-5-(trifluoromethyl) pyrimidine-2,4-diamine 0.003  2

N2-(2-chloro-4-(1- methyl-1H-tetrazol-5- yl)phenyl)-N4-methyl-5-(trifluoromethyl) pyrimidine-2,4-diamine 0.007  3

N2-(2-chloro-4-(2- methyl-2H-tetrazol-5- yl)phenyl)-N4-methyl-5-(trifluoromethyl) pyrimidine-2,4-diamine 0.018  4

N2-(2-methoxy-4-(1H- 1,2,4-triazol-1- yl)phenyl)-N4-methyl-5-(trifluoromethyl) pyrimidine-2,4-diamine 0.003  5

N2-(2-methoxy-4-(1- methyl-1H-pyrazol-4- yl)phenyl)-N4-methyl-5-(trifluoromethyl) pyrimidine-2,4-diamine 0.004  6

N2-(5-fluoro-2-methoxy- 4-(3-methyl-1,2,4- oxadiazol-5-yl)phenyl)-N4-methyl-5- (trifluoromethyl) pyrimidine-2,4-diamine 0.032  7

N2-(2-chloro-5-methoxy- 4-(5-methyl-1,3,4- oxadiazol-2-yl)phenyl)-N4-methyl-5- (trifluoromethyl) pyrimidine-2,4-diamine 0.008  8

N²-(2-methoxy-4-(1- methyl-1H-imidazol-5- yl)phenyl-N⁴-methyl-5-(trifluoromethyl) pyrimidine-2,4-diamine ¹H NMR (400 MHz, DMSO): δ 8.33(d, J = 8.3, 1 H); 8.21 (s, 1 H); 8.10 (s, 1 H); 7.72 (s, 1 H); 7.23 (d,J = 5.2, 1 H); 7.16-7.07 (m, 3 H); 3.95 (s, 3 H); 3.74 (s, 3 H); 2.96(d, J = 4.3, 3 H). 0.002  9

N²-(4-methoxy-6- (thiazol-5-yl)pyridin-3- yl)-N⁴-methyl-5-(trifluoromethyl) pyrimidine-2,4-diamine ¹H NMR δ (ppm)(CHCl3- d): 9.65(1 H, s), 8.9 (1 H, d, J = 2.14 Hz), 8.2 (1 H, d, J = 1.09 Hz), 8.1 (1H, d, J = 2.14 Hz), 7.75 (1 H, s), 7.55 (1 H, s), 5.27 (1 H, s), 4.1 (3H, s), 3.2 (3 H, d, J = 4.72 Hz) 10

5-chloro-N²-(2-methoxy- 4-(1-methyl-1H-tetrazol- 5- yl)phenyl)-N⁴-methylpyrimidine-2,4- diamine ¹H NMR (400 MHz, CDCl3): δ 8.76 (d, J =8.5 Hz, 1 H); 7.96 (s, 1 H); 7.75 (s, 1 H); 7.40 (d, J = 1.9 Hz, 1 H);7.3 (d, 1 H); 5.35 (s, 1 H); 4.21 (s, 3 H); 4.00 (s, 3 H); 3.13 (d, J =4.9 Hz, 3 H). 0.007 11

N²-(2-chloro-5-methoxy- 4-(1-methyl-1H-1,2,3- triazol-5-yl)phenyl)-N⁴-methyl-5- (trifluoromethyl) pyrimidine-2,4-diamine ¹H NMR δ (DMSO-d₆):8.58 (s, 1 H); 8.16 (s, 1 H); 7.98 (s, 1 H); 7.71 (s, 1 H); 7.42 (s, 1H); 7.24 (d, J = 5.1 Hz, 1H); 3.82 (s, 3 H); 3.76 (s, 3 H); 2.87 (d, J =4.4 Hz, 3 H). 0.004 12

N²-(4-methoxy-6- (thiazol-4-yl)pyridin-3- yl)-N⁴-methyl-5-(trifluoromethyl) pyrimidine-2,4-diamine 13

N²-(4-methoxy-6- (oxazol-2-yl)pyridin-3- yl)-N⁴-methyl-5-(trifluoromethyl) pyrimidine-2,4-diamine 14

5-chloro-N²-(4-(isoxazol- 4-yl)-2-methoxyphenyl)-N⁴-methylpyrimidine-2,4- diamine ¹H NMR (400 MHz, CDCl₃): δ 8.64 (s, 1H); 8.59 (d, J = 8.4, 1 H); 8.56 (s, 1 H); 7.95-7.92 (m, 1 H); 7.62 (s,1 H); 7.12 (dd, J = 8.4, 1.9, 1 H); 6.96 (d, J = 1.9, 1 H); 5.32 (s, 1H); 3.98 (s, 3 H); 3.14 (d, J = 4.9, 3 H). 0.015 15

5-chloro-N²-(2-methoxy- 4-(1-methyl-1H- imidazol-2-yl)phenyl)-N⁴-methylpyrimidine-2,4- diamine ¹H NMR (400 MHz, CDCl₃): δ 8.65 (d, J =8.3, 1 H); 7.96 (s, 1 H); 7.85 (s, 1 H); 7.70 (s, 1 H); 7.18 (s, 1 H);7.01 (d, J = 8.9, 1 H); 6.89 (s, 1 H); 5.35 (s, 1 H); 3.96 (s, 3 H);3.75 (s, 3 H); 3.15 (d, J = 4.9, 3 H). 0.007 16

5-chloro-N2-(2-methoxy- 4-(1-methyl-1H- imidazol-5-yl)phenyl)-N4-methylpyrimidine- 2,4-diamine ¹H NMR (400 MHz, CDCl₃): δ 8.61 (d, J =8.3, 1 H); 7.95 (s, 1 H); 7.62 (s, 1 H); 7.52 (s, 1 H); 7.09 (s, 1 H);7.01 (dd, J = 8.4, 1.9, 1 H); 6.90 (d, J = 1.9, 1 H); 5.32 (s, 1 H);3.95 (s, 3 H); 3.69 (s, 3 H); 3.15 (d, J = 4.9, 3 H). 0.002 17

N²-(2-methoxy-4-(1- methyl-1H-1,2,3-triazol- 5-yl)phenyl)-N⁴-methyl- 5-(trifluoromethyl) pyrimidine-2,4-diamine 0.002 18

N²-(2-methoxy-4-(2- methyl-2H-tetrazol-5- yl)phenyl)-N⁴-methyl-5-(trifluoromethyl) pyrimidine-2,4-diamine ¹H NMR (400 MHz, CDCl3): δ 8.68(d, J = 8.5 Hz, 1 H); 8.20 (s, 1 H); 7.88 (s, 1 H); 7.78 (dd, J = 8.5,1.8 Hz, 1 H); 7.67 (d, J = 1.8 Hz, 1 H); 5.24 (s, 1 H); 4.39 (s, 3 H);4.01 (s, 3 H); 3.14 (d, J = 4.7 Hz, 3 H). 0.010 19

N²-(2-chloro-5-methoxy- 4-(1-methyl-1H- imidazol-2-yl)phenyl)-N⁴-methyl-5- (trifluoromethyl) pyrimidine-2,4-diamine ¹H NMR (400 MHz,DMSO): δ 8.69 (s, 1 H); 8.48 (s, 1 H); 8.25 (s, 1 H); 8.04 (s, 1 H);7.46 (s, 1 H); 7.40-7.30 (m, 2 H); 3.85 (s, 3 H); 3.61 (s, 3 H); 2.95(d, J = 4.4, 3H). 0.003 20

N²-(2-methoxy-4-(1- methyl-1H-tetrazol-5- yl)phenyl)-N⁴-methyl-5-(trifluoromethyl) pyrimidine-2,4-diamine ¹H NMR (400 MHz, CDCl3): δ 8.78(d, J = 8.5 Hz, 1 H); 8.22 (s, 1 H); 7.93 (s, 1 H); 7.42 (d, J = 1.9 Hz,1 H); 7.28 (dd, J = 8.5, 1.9 Hz, 1 H); 5.28 (s, 1 H); 4.22 (s, 3 H);4.01 (s, 3 H); 3.14 (d, J = 4.7 Hz, 3 H). 0.003 21

N²-(2-chloro-5-methoxy- 4-(1-methyl-1H- imidazol-5-yl)phenyl)-N⁴-methyl-5- (trifluoromethyl) pyrimidine-2,4-diamine ¹H NMR (400 MHz,DMSO): δ 8.64 (s, 1 H); 8.24 (s, 1 H); 7.96 (s, 1 H); 7.73 (s, 1 H);7.36 (s, 1 H); 7.29 (d, J = 5.2, 1 H); 6.95 (s, 1 H); 3.83 (s, 3 H);3.51 (s, 3 H); 2.96 (d, J = 4.2, 3 H). 0.003 22

N²-(5-fluoro-2-methoxy- 4-(1-methyl-1H-tetrazol- 5-yl)phenyl)-N⁴-methyl-5- (trifluoromethyl) pyrimidine-2,4-diamine 0.010 23

5-chloro-N²-(2-methoxy- 4-(1-methyl-1H-1,2,3- triazol-5-yl)phenyl)-N⁴-methylpyrimidine-2,4- diamine 0.003 24

N²-(2-chloro-5-methoxy- 4-(1,3,5-trimethyl-1H- pyrazol-4-yl)phenyl)-N⁴-methyl-5- (trifluoromethyl) pyrimidine-2,4-diamine 0.003 25

N²-(2-methoxy-4-(1- methyl-1H-pyrazol-5- yl)phenyl)-N⁴-methyl-5-(trifluoromethyl) pyrimidine-2,4-diamine 0.001 26

N²-(4-(3,5- dimethylisoxazol-4-yl)-2- methoxyphenyl)-N⁴- methyl-5-(trifluoromethyl) pyrimidine-2,4-diamine ¹H NMR (400 MHz, CDCl3): δ 8.59(d, J = 8.3 Hz, 1 H); 8.19 (s, 1 H); 7.78 (s, 1 H); 6.87 (dd, J = 8.3,1.9 Hz, 1 H); 6.76 (d, J = 1.9 Hz, 1 H); 5.23 (s, 1 H); 3.93 (s, 3 H);3.13 (d, J = 4.7 Hz, 3 H); 2.42 (s, 3 H); 2.29 (s, 3 H). 0.001 27

N²-(2-methoxy-4-(1H- tetrazol-1-yl)phenyl)-N⁴- methyl-5-(trifluoromethyl) pyrimidine-2,4-diamine ¹H NMR (400 MHz, CDCl₃): δ 8.95(s, 1H), 8.78 (d, J = 8.7 Hz, 1H), 8.21 (d, J = 1.1 Hz, 1H), 7.84 (s,1H), 7.30 (d, J = 2.4 Hz, 1H), 7.22 (dd, J = 8.8, 2.4 Hz, 1H), 5.28 (brs, 1H), 4.02 (s, 3H), 3.14 (d, J = 4.7 Hz, 3H). 0.002 28

N²-(2-chloro-5-methoxy- 4-(1-methyl-1H-pyrazol- 5-yl)phenyl)-N⁴-methyl-5- (trifluoromethyl) pyrimidine-2,4-diamine 0.005 29

N⁴-ethyl-N²-(5-fluoro-2- methoxy-4-(5-methyl- 1,3,4-oxadiazol-2-yl)phenyl)-5- (trifluoromethyl) pyrimidine-2,4-diamine ¹H NMR (400 MHz,CDCl₃): δ 8.61 (d, J = 13.5, 1H); 8.22 (s, 1H); 7.94 (s, 1H); 7.47 (d, J= 6.2, 1H); 5.25 (s, 1H); 3.99 (s, 3H); 3.68-3.60 (m, 2H); 2.64 (s, 3H);1.35 (t, J = 7.2, 3H). 0.007 30

N²-(5-fluoro-2-methoxy- 4-(5-methyl-1,3,4- oxadiazol-2-yl)phenyl)-N⁴-methyl-5- (trifluoromethyl) pyrimidine-2,4-diamine ¹H NMR (400 MHz,CDCl₃): δ 8.64 (d, J = 13.4, 1H); 8.22 (s, 1H); 7.97 (s, 1H); 7.48 (d, J= 6.2, 1H); 5.32 (s, 1H); 3.99 (s, 3H); 3.15 (d, J = 4.7, 3H); 2.64 (s,3H). 0.012 31

N²-(2-chloro-5-methoxy- 4-(3-methyl-1,2,4- oxadiazol-5-yl)phenyl)-N⁴-methyl-5- (trifluoromethyl) pyrimidine-2,4-diamine ¹H NMR (400 MHz,CDCl₃): δ 8.65 (s, 1H); 8.26 (s, 1H); 8.11 (s, 1H); 7.85 (s, 1H); 5.35(s, 1H); 4.03 (s, 3H); 3.15 (d, J = 4.7, 3H); 2.48 (s, 3H). 0.041 32

N²-(2-chloro-5-methoxy- 4-(1-methyl-1H-pyrazol- 4-yl)phenyl)-N⁴-methyl-5- (trifluoromethyl) pyrimidine-2,4-diamine ¹H NMR (400 MHz, CDCl₃): δ8.35 (s, 1H); 8.21 (s, 1H); 7.81 (d, J = 9.7, 2H); 7.59 (s, 1H); 7.50(s, 1H); 5.27 (s, 1H); 3.97-3.88 (m, 6H); 3.13 (d, J = 4.7, 3H). 0.01133

5-chloro-N²-(2-chloro-4- (5-methyl-1,3,4- oxadiazol-2-yl)phenyl)-N⁴-methylpyrimidine-2,4- diamine ¹H NMR (400 MHz, CDCl₃): δ 8.82 (d, J =8.8, 1H); 8.05 (d, J = 2.0, 1H); 7.98-7.90 (m, 2H); 7.62 (s, 1H); 5.39(s, 1H); 3.12 (d, J = 4.9, 3H); 2.61 (s, 3H). 0.030 34

5-chloro-N²-(2-chloro-4- (3-methyl-1,2,4- oxadiazol-5-yl)phenyl)-N⁴-methylpyrimidine-2,4- diamine ¹H NMR (400 MHz, CDCl₃): δ 8.86 (d, J =8.8, 1H); 8.15 (d, J = 2.0, 1H); 8.03-7.97 (m, 2H); 7.68 (s, 1H); 5.40(s, 1H); 3.12 (d, J = 4.9, 3H); 2.46 (s, 3H). 0.08 35

5-chloro-N²-(2-methoxy- 4-(1-methyl-1H-pyrazol- 4-yl)phenyl)-N⁴-methylpyrimidine-2,4- diamine ¹H NMR (400 MHz, CDCl₃): δ 8.48 (d, J =8.4, 1H); 7.91 (s, 1H); 7.72 (s, 1H); 7.57 (s, 1H); 7.52 (s, 1H); 7.09(dd, J = 8.4, 1.9, 1H); 6.96 (d, J = 1.9, 1H); 5.32-5.20 (m, 1H), 3.94(d, J = 1.9, 6H); 3.12 (d, J = 4.9, 3H). 0.002 36

5-chloro-N²-(2-chloro-5- methoxy-4-(3-methyl- 1,2,4-oxadiazol-5-yl)phenyl)-N⁴- methylpyrimidine-2,4- diamine ¹H NMR (400 MHz, CDCl₃): δ8.66 (s, 1H); 8.08 (s, 1H); 8.00 (s, 1H); 7.70 (s, 1H); 5.43 (d, J =5.9, 1H); 4.03 (s, 3H); 3.13 (t, J = 4.9, 3H); 2.47 (s, 3H). 0.044 37

5-chloro-N²-(2-chloro-5- methoxy-4-(5-methyl- 1,3,4-oxadiazol-2-yl)phenyl)-N⁴- methylpyrimidine-2,4- diamine ¹H NMR (400 MHz, CDCl₃): δ8.64 (s, 1H); 7.99 (s, 1H); 7.92 (s, 1H); 7.64 (s, 1H); 5.42 (s, 1H);4.01 (s, 3H); 3.14 (d, J = 4.9, 3H); 2.61 (s, 3H). 0.012 38

N2-(4-(1,3-dimethyl-1H- pyrazol-4-yl)-2- methoxyphenyl)-N4- methyl-5-(trifluoromethyl) pyrimidine-2,4-diamine 0.002 39

N2-(4-(1,5-dimethyl-1H- pyrazol-4-yl)-2- methoxyphenyl)-N4- methyl-5-(trifluoromethyl) pyrimidine-2,4-diamine 0.003 40

N2-(2-methoxy-4-(4- methyl-4H-1,2,4-triazol- 3-yl)phenyl)-N4-methyl- 5-(trifluoromethyl) pyrimidine-2,4-diamine 0.002 41

4-(2-fluoro-5-methoxy-4- (4-(methylamino)-5- (trifluoromethyl)pyrimidin-2-ylamino) phenyl)- N,N,1-trimethyl-1H- pyrazole-5-carboxamide0.001 42

N2-(5-fluoro-2-methoxy- 4-(5-methyl-1H-tetrazol- 1-yl)phenyl)-N4-methyl-5- (trifluoromethyl) pyrimidine-2,4-diamine 0.003 43

N2-(5-fluoro-2-methoxy- 4-(1-methyl-1H-1,2,3- triazol-5-yl)phenyl)-N4-methyl-5- (trifluoromethyl) pyrimidine-2,4-diamine 0.002 44

N2-(5-fluoro-2-methoxy- 4-(1-(oxetan-3-yl)-1H- pyrazol-4-yl)phenyl)-N4-methyl-5- (trifluoromethyl) pyrimidine-2,4-diamine 0.01 45

N2-(2-methoxy-5- methyl-4-(5-methyl-1H- tetrazol-1-yl)phenyl)-N4-methyl-5- (trifluoromethyl) pyrimidine-2,4-diamine 0.001 46

N2-(2-methoxy-4-(5- (methoxymethyl)-1H- tetrazol-1-yl)-5-methylphenyl)-N4- methyl-5- (trifluuromethyl) pyrimidine-2,4-diamine0.001 47

N2-(5-fluoro-2-methoxy- 4-(5-(methoxymethyl)-3- methyl-1H-pyrazol-1-yl)phenyl)-N4-methyl-5- (trifluoromethyl) pyrimidine-2,4-diamine 0.00548

N2-(2-methoxy-4-(5- (methoxymethyl)-3- methyl-1H-pyrazol-1-yl)phenyl)-N4-methyl-5- (trifluoromethyl) pyrimidine-2,4-diamine 0.01049

N2-(5-fluoro-2-methoxy- 4-(5-(methoxymethyl)- 1H-tetrazol-1-yl)phenyl)-N4-methyl-5- (trifluoromethyl) pyrimidine-2,4-diamine 0.004

Example 12 In Vitro LRRK2 LabChip Assay

This assay was used to determine a compound's potency in inhibitingactivity of LRRK2 by determining, Ki_(app), IC₅₀, or percent inhibitionvalues. In a polypropylene plate, LRRK2, fluorescently-labeled peptidesubstrate, ATP and test compound were incubated together. Using aLabChip 3000 (Caliper Life Sciences), after the reaction the substratewas separated by capillary electrophoresis into two populations:phosphorylated and unphosphorylated. The relative amounts of each werequantitated by fluorescence intensity. LRRK2 Ki was determined accordingto the equation:Y=V0*(1−((x+Ki*(1+S/Km)+Et)/(2*Et)−(((x+Ki*(1+S/Km)+Et)^2−(4*Et*x))^0.5)/(2*Et))).Ki values in Table 4 and elsewhere herein are shown in μM.

Assay conditions and materials used were as follows:

Final Assay Conditions:

LRRK2 G2019S in 5 mM MgCl₂: 5.2 nM (Invitrogen lot #567054A)

LRRK2 G2019S in 1 mM MnCl₂: 11 nM (Invitrogen lot #567054A)

LRRK2 Wild type in 5 mM MgCl₂: 15 nM (Invitrogen lot #500607F)

LRRK2 12020T in 5 mM MgCl₂: 25 nM (Invitrogen lot #43594)

Substrate: 1 μM

ATP: 130 μM

Kinase reaction time: 2 hours

Temperature: ambient

Total volume: 20 μl

ATP^(app) Kms:

G2019S in 5 mM MgCl₂: 130 μM

G2019S in 1 mM MnCl₂: 1 μM

Wild type in 5 mM MgCl₂: 80 μM

I2020T in 5 mM MgCl₂: 14 μM

Materials:

Solid Support: Black 50 μL volume polypropylene 384 well plate (MatriCalcat #MP101-1-PP)

Kinase: LRRK2 G2019S (Invitrogen cat #PV4882).

-   -   LRRK2 Wild type (Invitrogen cat #PV4874).

Substrate: 5FAM-GAGRLGRDKYKTLRQIRQ-CONH₂

Non-binding plate: 384 well clear V-bottom polypropylene plates (Greinercat #781280).

ATP: 10 mM ATP (Cell Signaling cat #9804).

Triton X-100: Triton X-100.

Brij-35: Brij-35 (Pierce cat #20150).

Coating Reagent #3: Coating Reagent #3 (Caliper).

DMSO: DMSO (Sigma cat #34869-100 ML).

Complete Reaction Buffer: H₂O/25 mM Tris, pH 8.0/5 mM MgCl₂/2 mMDTT/0.01% Triton X-100.

Stop Solution: H₂O/100 mM HEPES, pH 7.2/0.015% Brij-35/0.2% CoatingReagent #3/20 mM EDTA.

Separation Buffer: H₂O/100 mM HEPES, pH 7.2/0.015% Brij-35/0.1% CoatingReagent #3/1:200 Coating Reagent #8/10 mM EDTA/5% DMSO.

Compound Plate Preparation:

For serial dilutions, 34.6 μl DMSO was added to columns 3-24. For theassay controls, 37.5 μl DMSO was added to columns 1 and 2 of rows A andP. a,d and 50 μl 25 μM G-028831 (Staurosporine) was added to columns 1and 2, row B. For the samples: to start at 100 μM, 37.5 μl DMSO was tocolumns 1 and 2, then 12.5 μl 10 mM compound; to start at 10 μM, 78 μlDMSO was added to columns 1 & 2, then 2 μl 10 mM compound; and to startat 1 μM, 25 μM compound (2 μl 10 mM cmpd+798 μl DMSO) was added to emptycolumns 1 and 2. A Precision instrument was used to perform 1:3.16serial dilutions (“PLK_BM_serial_halflog”).

ATP Preparation:

ATP was diluted to 282.1 μM in Complete Kinase Buffer (finalconcentration was 130 μM).

Total and Blank Preparation:

In Complete Reaction Buffer, substrate was diluted to 4 μM. Equalvolumes of Complete Reaction Buffer and 4 μM substrate were combined toobtain the blank. Equal volumes of Complete Reaction Buffer and 4 μMsubstrate were combined and to the combined solution was added 2× finalLRRK2 concentration.

Assay Procedure:

To a 50 μl polypropylene plate, 5 μl/well buffer/substrate was added byhand to Blank wells. A Biomek FX was used to start the kinase reaction(“PLK SAR 23 ATP”). The following were added to the appropriate wells:

2 μl compound+23 μl ATP;

5 μl/well compound/ATP in Assay Plate;

5 μl/well kinase/substrate in Assay Plate;

The plate was incubated for 2 hours in the dark. Biomek FX was used tostop the kinase reaction (“PLK Stop”), and 10 μl/well Stop solution wasadded to the Assay Plate. Results were read on the LabChip 3000.

Lab Chip 3000 Protocol:

The LabChip 3000 was run using the job “LRRK2 IC50” with the followingjob settings:

Pressure: −1.4 psi

Downstream voltage: −500 V

Upstream voltage: −2350 V

Post sample buffer sip time: 75 seconds

Post dye buffer sip time: 75 seconds

Final delay time: 200 seconds

Example 13 In Vitro LRRK2 Lanthascreen Binding Assay

This assay was used to determine a compound's potency in inhibitingactivity of LRRK2 by determining, Ki_(app), IC₅₀, or percent inhibitionvalues. In 384 well proxiplates F black, shallow well plates LRRK2,Eu-anti-GST-antibody, Alexa Fluor® Kinase tracer 236 and test compoundwere incubated together.

Binding of the Alexa Fluor® “tracer” to a kinase was detected byaddition of a Eu-labeled anti-GST antibody. Binding of the tracer andantibody to a kinase results in a high degree of FRET, whereasdisplacement of the tracer with a kinase inhibitor results in a loss ofFRET.

Assay conditions and materials used were as follows:

Final Assay Conditions:

GST-LRRK2 G2019S 10 nM

Eu-anti-GST-antibody 2 nM

Kinase tracer 236 8.5 nM

Kinase reaction time: 1 hour

Temperature: ambient

Total volume: 15 μl

DMSO 1%

Materials:

384 well proxiplates F black shallow well Perkin Elmer cat#6008260

Kinase: LRRK2 G2019S Invitrogen cat #PV4882 (LOT 567054A).

Eu-labeled anti-GST antibody Invitrogen cat #PV5594

Alexa Fluor® Kinase tracer 236 Invitrogen cat #PV5592

TRIS-HCl Sigma cat #T3253

EGTA Sigma cat #E3889

Brij-35: Sigma cat #B4184 (30% w/v)

DMSO: Sigma cat #D8418

MgCl₂ Sigma cat #M9272

Reaction Buffer: H₂O/50 mM Tris, pH 7.4/10 mM MgCl₂/1 mM EGTA/0.01% Brij35.

Compound Plate Preparation:

Serially dilute test compounds (10 mM stock) 1:3.16 (20 ul+43.2 ul) in100% DMSO. 12 pt curve. Dilute each concentration 1:33.3 (3 ul+97 ul) inreaction buffer. Stamp 5 ul to assay plate. Final top test concentration100 uM.

Total and Blank Preparation:

In Reaction Buffer, 5 ul of DMSO (3%) was added to total and blank wellsand 5 ul of Eu-labeled anti-GST antibody (6 nM) was added to blankwells.

Assay Procedure:

Add 5 ul LRRK2 (30 nM)/Eu-labeled anti-GST antibody (6 nM) mix tocompound and total wells. Add 5 ul kinase tracer (25.5 nM) to all wells.Incubate plates at room temperature for 1 hour on a plate shaker (gentleshaking). Read on Perkin Elmer EnVision reader HTRF protocol.

Data Handling:

Calculate ratio: (665/620)*10000. Subtract mean background values fromall data points. Calculate % of control for each test value. Plot % ofcontrol vs Compound concentration. Calculate Ki Value (xlfit curvefitting—Morrison equation).

Results expressed as a Ki in 1 μM. The equation for Ki:Y=V0*(1−((x+Ki*(1+S/Km)+Et)/(2*Et)−(((x+Ki*(1+S/Km)+Et)^2−(4*Et*x))^0.5)/(2*Et)))

Where Et=4 nM

kd (Tracer)=8.5 nM

Tracer concentration (S)=8.5 nM.

Example 14 Parkinson's Disease Animal Model

Parkinson's disease can be replicated in mice and in primates byadministration of 1-methyl-4-phenyl tetrahydropyridine (MPTP), aselective nigrostriatal dopaminergic neurotoxin that produces a loss ofstriatal dopamine (DA) nerve terminal markers. Compounds of theinvention may be evaluated for effectiveness in treatment of Parkinson'sdisease using MPTP induced neurodegeneration following generally theprotocol described by Saporito et al., J. Pharmacology (1999) Vol. 288,pp. 421-427.

Briefly, MPTP is dissolved in PBS at concentrations of 2-4 mg/ml, andmice (male C57 weighing 20-25 g) are given a subcutaneous injection of20 to 40 mg/kg. Compounds of the invention are solubilized withpolyethylene glycol hydroxystearate and dissolved in PBS. Mice areadministered 10 ml/kg of compound solution by subcutaneous injection 4to 6 h before MPTP administration, and then daily for 7 days. On the dayof the last injection, mice are sacrificed and the midbrain blocked andpostfixed in paraformaldehyde. Striata are dissected free, weighed, andstored at −70° C.

The striata thus collected are evaluated for content of dopamine and itsmetabolites dihydroxyphenylacetic acid and homovanillic acid, by HPLCwith electrochemical detection as described by Sonsalla et al., J.Pharmacol. Exp. Ther. (1987) Vol. 242, pp. 850-857. The striata may alsobe evaluated using the tyrosine hydroxylase assay of Okunu et al., AnalBiochem (1987) Vol. 129, pp. 405-411 by measuring ¹⁴CO₂ evolutionassociated with tyrosine hydroxylase-mediated conversion of labeledtyrosine to L-dopa. The striata may further be evaluated using theMonoamine oxidase-B assay as described by White et al., Life Sci.(1984), Vol. 35, pp. 827-833, and by monitoring dopamine uptake asdescribed by Saporito et al., (1992) Vol. 260, pp. 1400-1409.

While the present invention has been described with reference to thespecific embodiments thereof, it should be understood by those skilledin the art that various changes may be made and equivalents may besubstituted without departing from the true spirit and scope of theinvention. In addition, many modifications may be made to adapt aparticular situation, material, composition of matter, process, processstep or steps, to the objective spirit and scope of the presentinvention. All such modifications are intended to be within the scope ofthe claims appended hereto.

What is claimed is:
 1. A compound of formula I:

or pharmaceutically acceptable salts thereof, wherein: m is from 0 to 3;X is: —NR^(a)—; —O—; or —S(O)_(r)— wherein r is from 0 to 2 and R^(a) ishydrogen or C₁₋₆alkyl; Y is C or N; R¹ is: C₁₋₆; or R¹ and R^(a)together with the atoms to which they are attached may form a three tosix membered ring that may optionally include an additional heteroatomselected from O, N and S, and which is substituted with oxo, halo orC₁₋₆alkyl; R² is: halo; C₁₋₆alkoxy; cyano; C₁₋₆alkynyl; C₁₋₆alkenyl;halo-C₁₋₆alkyl; halo-C₁₋₆alkoxy; C₃₋₆cycloalkyl wherein theC₃₋₆cycloalkyl portion is optionally substituted with C₁₋₆alkyl;C₃₋₆cycloalkyl-C₁₋₆alkyl wherein the C₃₋₆cycloalkyl portion isoptionally substituted with C₁₋₆alkyl; tetrahydrofuranyl;tetrahydrofuranyl-C₁₋₆alkyl; acetyl; oxetanyl; or oxetan-C₁₋₆alkyl; R³and R⁴ each independently is: halo; C₁₋₆alkyl; C₁₋₆alkoxy;C₃₋₆cycloalkyloxy; halo-C₁₋₆alkyl; or halo-C₁₋₆alkoxy; and R⁵ is a5-membered heteroaryl group optionally substituted one or more timeswith R⁶; and R⁶ is: C₁₋₆alkyl; C₃₋₆cycloalkyl; C₃₋₆cycloalkyl-C₁₋₆alkyl;halo; halo-C₁₋₆alkyl; C₁₋₆alkoxy; heterocyclyl; oxo; or—C(O)—NR^(b)R^(c) wherein R^(b) and R^(c) each independently is hydrogenor —C₁₋₆alkyl.
 2. The compound of claim 1, wherein X is —NH— or —O—. 3.The compound of claim 1, wherein R¹ is: C₁₋₆alkyl; C₃₋₆cycloalkyloptionally substituted with C₁₋₆alkyl; or C₃₋₆cycloalkyl-C₁₋₆alkylwherein the C₃₋₆cycloalkyl portion is optionally substituted withC₁₋₆alkyl.
 4. The compound of claim 1, wherein R¹ is methyl or ethyl. 5.The compound of claim 1, wherein R² is: halo; halo-C₁₋₆alkyl; or cyano.6. The compound of claim 1, wherein R² is chloro or trifluoromethyl. 7.The compound of claim 1, wherein R³ is halo or C₁₋₆alkoxy.
 8. Thecompound of claim 1, wherein R³ is methoxy.
 9. The compound of claim 1,wherein m is 0 or
 1. 10. The compound of claim 1, wherein R⁴ is halo ormethoxy.
 11. The compound of claim 1, wherein R⁵ is: pyrazolyl;imidazolyl; oxadiazolyl; thiadiazolyl; triazolyl; or tetrazolyl; eachoptionally substituted one or more times with R⁶.
 12. The compound ofclaim 1, wherein R⁵ is: pyrazolyl; oxadiazolyl; triazolyl; ortetrazolyl; each optionally substituted one or more times with R⁶. 13.The compound of claim 1, wherein R⁵ is: oxadiazolyl; triazolyl; ortetrazolyl; each optionally substituted one or more times with R⁶. 14.The compound of claim 1, wherein R⁵ is pyrazolyl optionally substitutedone or more times with R⁶.
 15. The compound of claim 1, wherein R⁵ isoxadiazolyl; thiadiazolyl; triazolyl; or tetrazolyl; optionallysubstituted one or more times with R⁶.
 16. The compound of claim 1,wherein R⁵ is triazolyl optionally substituted one or more times withR⁶.
 17. The compound of claim 1, wherein R⁵ is tetrazolyl optionallysubstituted one or more times with R⁶.
 18. The compound of claim 1,wherein R⁵ is: 1-methyl-1H-imidazol-2-yl; 1-methyl-1H-imidazol-5-yl;1,3,5-trimethyl-1H-pyrazol-4-yl; 1-methyl-1H-pyrazol-5-yl;1-methyl-1H-pyrazol-4-yl; 1,3-dimethyl-1H-pyrazol-4-yl;1,5-dimethyl-1H-pyrazol-4-yl;5-(dimethylaminocarbonyl)-1-methyl-1H-pyrazol-4-yl;1-(oxetan-3-yl)-1H-pyrazol-4-yl;5-(methoxymethyl)-3-methyl-1H-pyrazol-1-yl;1-methyl-1H-1,2,3-triazol-5-yl; 1H-1,2,4-triazol-1-yl;4-methyl-4H-1,2,4-triazol-3-yl; 5-methyl-1,3,4-oxadiazol-2-yl;3-methyl-1,2,4-oxadiazol-5-yl; 1-methyl-1H-tetrazol-5-yl;2-methyl-2H-tetrazol-5-yl; 1H-tetrazol-1-yl; 2H-tetrazol-5-yl;5-methyl-1H-tetrazol-1-yl; or 5-(methoxymethyl)-1H-tetrazol-1-yl.
 19. Acomposition comprising: (a) a pharmaceutically acceptable carrier; and(b) a compound of claim
 1. 20. A method for treating Parkinson'sdisease, said method comprising administering to a subject in needthereof an effective amount of a compound of claim
 1. 21. The compoundof claim 1, wherein said compound selected from:N²-(2-chloro-4-(2H-tetrazol-5-yl)phenyl)-N⁴-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine;N²-(2-chloro-4-(1-methyl-1H-tetrazol-5-yl)phenyl)-N⁴-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine;N²-(2-chloro-4-(2-methyl-2H-tetrazol-5-yl)phenyl)-N⁴-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine;N²-(2-methoxy-4-(1H-1,2,4-triazol-1-yl)phenyl)-N⁴-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine;N²-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-N⁴-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine;N²-(5-fluoro-2-methoxy-4-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl)-N⁴-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine;N²-(2-chloro-5-methoxy-4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)-N⁴-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine;N²-(2-methoxy-4-(1-methyl-1H-imidazol-5-yl)phenyl)-N⁴-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamineN²-(4-methoxy-6-(thiazol-5-yl)pyridin-3-yl)-N⁴-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine;5-chloro-N²-(2-methoxy-4-(1-methyl-1H-tetrazol-5-yl)phenyl)-N⁴-methylpyrimidine-2,4-diamineN²-(2-chloro-5-methoxy-4-(1-methyl-1H-1,2,3-triazol-5-yl)phenyl)-N⁴-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine;N²-(4-methoxy-6-(thiazol-4-yl)pyridin-3-yl)-N⁴-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamineN²-(4-methoxy-6-(oxazol-2-yl)pyridin-3-yl)-N⁴-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine;5-chloro-N²-(4-(isoxazol-4-yl)-2-methoxyphenyl)-N⁴-methylpyrimidine-2,4-diamine;5-chloro-N²-(2-methoxy-4-(1-methyl-1H-imidazol-2-yl)phenyl)-N⁴-methylpyrimidine-2,4-diamine;5-chloro-N²-(2-methoxy-4-(1-methyl-1H-imidazol-5-yl)phenyl)-N⁴-methylpyrimidine-2,4-diamine;N²-(2-methoxy-4-(1-methyl-1H-1,2,3-triazol-5-yl)phenyl)-N⁴-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine;N²-(2-methoxy-4-(2-methyl-2H-tetrazol-5-yl)phenyl)-N⁴-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine;N²-(2-chloro-5-methoxy-4-(1-methyl-1H-imidazol-2-yl)phenyl)-N⁴-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine;N²-(2-methoxy-4-(1-methyl-1H-tetrazol-5-yl)phenyl)-N⁴-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine;N²-(2-chloro-5-methoxy-4-(1-methyl-1H-imidazol-5-yl)phenyl)-N⁴-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine;N²-(5-fluoro-2-methoxy-4-(1-methyl-1H-tetrazol-5-yl)phenyl)-N⁴-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine;5-chloro-N²-(2-methoxy-4-(1-methyl-1H-1,2,3-triazol-5-yl)phenyl)-N⁴-methylpyrimidine-2,4-diamineN²-(2-chloro-5-methoxy-4-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl)-N⁴-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine;N²-(2-methoxy-4-(1-methyl-1H-pyrazol-5-yl)phenyl)-N⁴-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine;N²-(4-(3,5-dimethylisoxazol-4-yl)-2-methoxyphenyl)-N⁴-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine;N²-(2-methoxy-4-(1H-tetrazol-1-yl)phenyl)-N⁴-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamineN²-(2-chloro-5-methoxy-4-(1-methyl-1H-pyrazol-5-yl)phenyl)-N⁴-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine;N⁴-ethyl-N-(5-fluoro-2-methoxy-4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)-5-(trifluoromethyl)pyrimidine-2,4-diamine;N²-(5-fluoro-2-methoxy-4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)-N⁴-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine;N²-(2-chloro-5-methoxy-4-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl)-N⁴-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine;N²-(2-chloro-5-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-N⁴-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine;5-chloro-N²-(2-chloro-4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)-N⁴-methylpyrimidine-2,4-diamine;5-chloro-N²-(2-chloro-4-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl)-N⁴-methylpyrimidine-2,4-diamine;5-chloro-N²-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-N⁴-methylpyrimidine-2,4-diamine5-chloro-N²-(2-chloro-5-methoxy-4-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl)-N⁴-methylpyrimidine-2,4-diamine;5-chloro-N²-(2-chloro-5-methoxy-4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)-N⁴-methylpyrimidine-2,4-diamine;N²-(4-(1,3-dimethyl-1H-pyrazol-4-yl)-2-methoxyphenyl)-N⁴-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine;N²-(4-(1,5-dimethyl-1H-pyrazol-4-yl)-2-methoxyphenyl)-N⁴-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine;N²-(2-methoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-N⁴-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine;4-(2-fluoro-5-methoxy-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)phenyl)-N,N,1-trimethyl-1H-pyrazole-5-carboxamide;N²-(5-fluoro-2-methoxy-4-(5-methyl-1H-tetrazol-1-yl)phenyl)-N⁴-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine;N²-(5-fluoro-2-methoxy-4-(1-methyl-1H-1,2,3-triazol-5-yl)phenyl)-N⁴-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine;N²-(5-fluoro-2-methoxy-4-(1-(oxetan-3-yl)-1H-pyrazol-4-yl)phenyl)-N⁴-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine;N²-(2-methoxy-5-methyl-4-(5-methyl-1H-tetrazol-1-yl)phenyl)-N⁴-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine;N²-(2-methoxy-4-(5-(methoxymethyl)-1H-tetrazol-1-yl)-5-methylphenyl)-N⁴-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine;N²-(5-fluoro-2-methoxy-4-(5-(methoxymethyl)-3-methyl-1H-pyrazol-1-yl)phenyl)-v-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine;N²-(2-methoxy-4-(5-(methoxymethyl)-3-methyl-1H-pyrazol-1-yl)phenyl)-N⁴-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine;andN²-(5-fluoro-2-methoxy-4-(5-(methoxymethyl)-1H-tetrazol-1-yl)phenyl)-N⁴-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine.